Impact of clinically tested NEP/ACE inhibitors on tumor uptake of [111In-DOTA]MG11

Background: We have recently shown that treatment of mice with the neutral endopeptidase (NEP) inhibitor phosphoramidon (PA) improves the bioavailability and tumor uptake of biodegradable radiopeptides. For the truncated gastrin radiotracer [111In-DOTA]MG11 ([(DOTA)DGlu10]gastrin(10–17)), this method led to impressively high tumor-to-kidney ratios. Translation of this concept in the clinic requires the use of certified NEP inhibitors, such as thiorphan (TO) and its orally administered prodrug racecadotril (Race). Besides NEP, angiotensin-converting enzyme (ACE) has also been implicated in the catabolism of gastrin analogs. In the present study, we first compared the effects induced by NEP inhibition (using PA, TO, or Race) and/or by ACE inhibition (using lisinopril, Lis) on the biodistribution profile of [111In-DOTA]MG11 in mice. In addition, we compared the efficacy of PA and TO at different administered doses to enhance tumor uptake. Methods: [111In-DOTA]MG11 was coinjected with (a) vehicle, (b) PA (300 μg), (c) TO (150 μg), (d) Lis (100 μg), (e) PA (300 μg) plus Lis (100 μg), or (f) 30–40 min after intraperitoneal (ip) injection of Race (3 mg) in SCID mice bearing AR42J xenografts. In addition, [111In-DOTA]MG11 was coinjected with vehicle, or with progressively increasing amounts of PA (3, 30, or 300 μg) or TO (1.5, 15, and 150 μg) in SCID mice bearing twin A431-CCK2R(+/−) tumors. In all above cases, biodistribution was conducted at 4 h postinjection (pi). Results: During NEP inhibition, the uptake of [111In-DOTA]MG11 in the AR42J tumors impressively increased from 1.8 ± 1.0 % ID/g (controls) to 15.3 ± 4.7 % ID/g (PA) and 12.3 ± 3.6 % ID/g (TO), while with Race tumor values reached 6.8 ± 2.8 % ID/g. Conversely, Lis had no effect on tumor uptake and no additive effect when coinjected with PA. During the dose dependence study in mice, PA turned out to be more efficacious in enhancing tumor uptake of [111In-DOTA]MG11 in the CCK2R-positive tumors compared to equimolar amounts of TO. In all cases, renal accumulation remained low, resulting in notable increases of tumor-to-kidney ratios. Conclusions: This study has confirmed NEP as the predominant degrading enzyme of [111In-DOTA]MG11 and ruled out the involvement of ACE in the in vivo catabolism of the radiotracer. NEP inhibition with the clinically tested NEP

Localization of Tc-99m-GRP Analogs in GRPR-Expressing Tumors: Effects of Peptide Length and Neprilysin Inhibition on Biological Responses

The overexpression of gastrin-releasing peptide receptors (GRPRs) in frequently occurring human tumors has provided the opportunity to use bombesin (BBN) analogs as radionuclide carriers to cancer sites for diagnostic and therapeutic purposes. We have been alternatively exploring human GRP motifs of higher GRPR selectivity compared to frog BBN sequences aiming to improve pharmacokinetic profiles. In the present study, we compared two differently truncated human endogenous GRP motifs: GRP(14–27) and GRP(18–27). An acyclic tetraamine was coupled at the N-terminus to allow for stable binding of the SPECT radionuclide 99mTc. Their biological profiles were compared in PC-3 cells and in mice without or with coinjection of phosphoramidon (PA) to induce transient neprilysin (NEP) inhibitio

The effect of butorphanol on the incidence of dexmedetomidine-induced emesis in cats

Objective: Τo evaluate the antiemetic effect of butorphanol (BUT) when co-administered with dexmedetomidine (DEX) in cats. Study design: Double-blind, randomized controlled cross-over experimental study. Animals: Fourteen purpose-bred healthy Domestic Short Hair cats, seven females and seven males, aged median (range) 14-84 (78) months and weighing 1.7-5.5 (4.0) kg. Methods: Each cat received five different treatment protocols intramuscularly (IM): (A) 25 μg kg-1 DEX; (B) 20 μg kg-1 DEX and 0.2 mg kg-1 BUT; (C) 20 μg kg-1 DEX and 0.1 mg kg-1 BUT; (D) 25 μg kg-1 DEX and 0.2 mg kg-1 BUT; and (E) 20 μg kg-1 DEX. Episodes of emesis, incidence and severity of nausea, and time to lateral recumbency were recorded for a period of 8 minutes after treatment administration, and the sedation was scored at the end of this period. The Friedman test and the Cochran's Q-test were used to analyse the data. Significance was evaluated at the 5% level. Results: The proportion of cats that vomited was significantly lower with the treatment protocols that included BUT (B, C and D) compared with the protocols that included only DEX (A and E). The proportion of cats that had nausea was significantly higher with the protocols that included only DEX (A and E) compared with protocols B and D. Time to lateral recumbency (p = 0.09) and sedation score (p = 0.07) was not statistically different between the treatment protocols. Conclusions and clinical relevance: Butorphanol can be used to prevent emesis and reduce the incidence and the severity of nausea caused by DEX in cats. It seems that the combination of BUT and DEX is very useful not only when emesis could result in serious complications, but also to provide comfort and well-being in cats sedated for minor procedures. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia

Traditional uses, phytochemistry, and pharmacology of elegia species: A review

In South Africa, plants belonging to the Restionaceae family possess an ecological dom-inance. As a result, they have been the subject of numerous morphological, anatomical, and evo-lutionary studies. However, few studies have focused on their phytochemical profile and their potential pharmacological activities. The genus Elegia L. is the second largest of this family compris-ing 52 species, which are mainly used as materials for thatching. Limited studies on the chemical constituents of Elegia species and their importance as medicinal plants have been undertaken. This review provides constructive and extensive information about the botanical characterization, distribu-tion, traditional uses, phytochemistry and pharmacology of the genus Elegia. A comprehensive search of previously published literature was performed for studies on this genus, using databases with different key search words. This survey documented 52 Elegia species summarizing their previous taxonomic classification. In addition, 14 species were found to be studied for their phytochemical profile, revealing 14 chemical compounds. Concerning their biological activities, only one species (E. tectorum (L.f.) Moline and H.P.Linder) is reported for its anti-wrinkle activity. Moreover, two species are locally used for thatching and as materials for brooms. The present review highlights the Elegia genus as an important source of bioactive phytochemicals with flavonol glycosides being the main metabolites and reveals the uncharted territory of this genus for new research studies. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

In vivo inhibition of neutral endopeptidase enhances the diagnostic potential of truncated gastrin In-111-radioligands

Introduction: Radiolabeled gastrin analogs represent attractive candidates for diagnosis and therapy of cholecystokinin subtype-2 receptor (CCK2R)-expressing tumors. Radiolabeled des(Glu)(5)-gastrins show favorably low renal accumulation, but localize poorly in CCK2R-positive lesions. We introduce herein three truncated [DOTADGIu(10)]gastrin(10-17) analogs, with oxidation-susceptible Met(15) replaced by: Ahp(15) (1), Nle(15) (2), or Leu(15) (3), and study the profile of [In-111]1/2/3 during in vivo inhibition of neutral endopeptidase (NEP) in comparison to the non-truncated [In-111-DOTA,DGIu(5)]gastrin(5-17) ([111In]4) reference. Methods: Blood samples collected from mice 5 min postinjection (pi) of [In-111]1/2/3/4 without or with phosphoramidon (PA) coinjection were analyzed by RP-HPLC Biodistribution was conducted in SCID mice bearing A431-CCK2R(+) or AR42J xenografts 4 h after administration of [In-111]1/2/3/4 without or with PA coinjection. Results: Firstly, we observed remarkable increases in the amount of radiopeptides detected intact in the blood of PA-treated mice at 5 min pi compared to controls. Secondly, we noted impressive enhancement of [In-111]1/2/3 localization in AR42J and A431-CCIQR(+) tumors in mice after PA coinjection. Specifically, the uptake of [In-111]1 at 4 h pi increased from 2.6 +/- 03%ID/g to 13.3 +/- 3.5%ID/g in the AR42J tumors and from 43 +/- 0.6%ID/g to 20.4 +/- 3.6%ID/g in the A431-CCK2R(+) xenografts, with comparable improvements noted for [In-111]2 and [In-111] as well. Thirdly, renal uptake remained favorably low and unaffected by PA (<2.5%ID/g). Conversely, although the stability and tumor targeting of [In-111]4 improved, its high renal uptake (>85%ID/g) increased even further by PA (>140%ID/g). Conclusions: In situ inhibition of NEP represents a promising new tool to enhance the diagnostic efficacy of biodegradable gastrin radioligands in the visualization of CCK2R-positive lesions in man. (C) 2015 Elsevier Inc. All rights reserved

Optimal extent of initial parathyroid resection in patients with multiple endocrine neoplasia syndrome type 1: A meta-analysis

Background: Hyperparathyroidism is an almost universal feature of multiple endocrine neoplasia type 1 syndrome. We present a systematic review and meta-analysis of the postoperative outcomes of patients undergoing initial operative treatment of primary hyperparathyroidism complicating multiple endocrine neoplasia 1. Methods: A comprehensive literature search was performed with a priori defined exclusion criteria for studies comparing total parathyroidectomy, subtotal parathyroidectomy, and less than subtotal parathyroidectomy. Results: Twenty-one studies incorporating 1,131 patients (272 undergoing total parathyroidectomy, 510 subtotal parathyroidectomy, and 349 less than subtotal parathyroidectomy) were identified. Pooled results revealed increased risk for long-term hypoparathyroidism in total parathyroidectomy patients (relative risk 1.61; 95% confidence interval, 1.12−2.31; P =.009) versus those undergoing subtotal parathyroidectomy. In the less than subtotal parathyroidectomy or subtotal parathyroidectomy comparison group, a greater risk for recurrence of hyperparathyroidism (relative risk 1.37; 95% confidence interval, 1.05−1.79; P =.02), persistence of hyperparathyroidism (relative risk 2.26; 95% confidence interval, 1.49−3.41; P =.0001), and reoperation for hyperparathyroidism (relative risk 2.48; 95% confidence interval, 1.65−3.73; P <.0001) was noted for less than subtotal parathyroidectomy patients, albeit with lesser risk for long-term for hypoparathyroidism (relative risk 0.47; 95% confidence interval, 0.29−0.75; P =.002). Conclusion: Subtotal parathyroidectomy compares favorably to total parathyroidectomy, exhibiting similar recurrence and persistence rates with a decreased propensity for long-term postoperative hypoparathyroidism. The benefit of the decreased risk of hypoparathyroidism in less than subtotal parathyroidectomy is negated by the increase in the risk for recurrence, persistence, and reoperation. Future studies evaluating the performance of less than subtotal parathyroidectomy in specific multiple endocrine neoplasia 1 phenotypes should be pursued in an effort to delineate a patient-tailored, operative approach that optimizes long-term outcomes. © 2020 Elsevier Inc