Search

19‐Norandrosterone (19NA) is the preferred urinary target compound to identify doping with nandrolone or related 19‐norsteroids. At concentrations between 2.5 and 15 ng/mL, isotope ratio mass spectrometry (IRMS) is required to establish exogenous origin of urinary 19NA. An absolute difference of 3‰ between urinary 19NA and an endogenous reference compound (ERC) constitutes a finding for exogenous origin of 19NA. Over the last 3 years, 77 samples containing urinary 19NA between 2.5 and 15 ng/mL were analyzed at our laboratory. The measured δ13C values for 19NA ranged from −29.5‰ to −16.8‰. In comparison, the δ13C values for the corresponding urinary ERCs ranged from −22.4‰ to −16.2‰. Due to the considerable overlap in values between the target compound and the natural range of urinary ERCs, it can be challenging to distinguish between endogenous and exogenous origins of urinary 19NA. In addition, it is well known that consumption of offal from non‐castrated pigs can produce 19NA in urine. To determine whether this could cause a positive IRMS finding under the current IRMS positivity criteria, meat from non‐castrated boars fed a mixture of corn and soy was consumed by 13 volunteers. Two volunteers produced 19NA findings above 2.5 ng/mL, and the measured isotope values, while inconsistent with documented 19‐norsteroid preparations, did meet IRMS positivity criteria. However, these increases in 19NA urinary concentrations were short‐lived due to rapid elimination. Timely follow‐up collections may help support a claim for dietary exposure when low urinary concentrations of 19NA with pseudo‐endogenous isotope values are observed. [ABSTRACT FROM AUTHOR]

pH dependence of bone resorption: mouse calvarial osteoclasts are activated by acidosis. Am J Physiol Endocrinol Metab 280: E112-E119, 2001.--We examined the effects of [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] and [CO.sub.2] acidosis on osteoclast-mediated [Ca.sup.2+] release from 3-day cultures of neonatal mouse calvaria. [Ca.sup.2+] release was minimal above pH 7.2 in control cultures but was stimulated strongly by the addition of small amounts of [H.sup.+] to culture medium ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] acidosis. For example, addition of 4 meq/l [H.sup.+] reduced pH from 7.12 to 7.03 and increased [Ca.sup.2+] release 3.8-fold. The largest stimulatory effects (8- to 11-fold), observed with 15-16 meq/l added [H.sup.+], were comparable to the maximal [Ca.sup.2+] release elicited by 1,25-dihydroxyvitamin [D.sub.3] [1,25[(OH).sub.2][D.sub.3]; 10 nM], parathyroid hormone (10 nM), or prostaglandin [E.sub.2] (1 [micro]M); the action of these osteolytic agents was attenuated strongly when ambient pH was increased from ~7.1 to -7.3. [CO.sub.2] acidosis was a less effective stimulator of [Ca.sup.2+] release than [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] acidosis over a similar pH range. [Ca.sup.2+] release stimulated by [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] acidosis was almost completely blocked by salmon calcitonin (20 ng/ml), implying osteoclast involvement. In whole mount preparations of control half-calvaria, ~400 inactive osteoclast-like multinucleate cells were present; in calvaria exposed to [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] acidosis and to the other osteolytic agents studied, extensive osteoclastic resorption, with perforation of bones, was visible. [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] acidosis, however, reduced numbers of osteoclast-like cells by ~50%, whereas 1,25[(OH).sub.2][D.sub.3] treatment caused increases of ~75%. The results suggest that [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] acidosis stimulates resorption by activating mature osteoclasts already present in calvarial bones, rather than by inducing formation of new osteoclasts, and provide further support for the critical role of acid-base balance in controlling osteoclast function. calcium release; carbon dioxide; bicarbonate ion; acid-base balance; osteolysis

Purpose: Osteoclast activity is an important factor in the pathogenesis of skeletal metastases and is a potential therapeutic target. This study aimed to determine if selective uptake of 99mTc-maraciclatide, a radiopharmaceutical targeting αvβ3 integrin, occurs in prostate cancer (PCa) bone metastases and to observe the changes following systemic therapy.Methods: The study group comprised 17 men with bone-predominant metastatic PCa who underwent whole-body planar and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging with 99mTc-maraciclatide before (n = 17) and 12 weeks after (n = 11) starting treatment with abiraterone. Tumour to normal bone (T:N) ratios, tumour to muscle (T:M) ratios and CT Hounsfield units (HU) were measured in up to five target metastases in each subject. An oncologist blinded to study scans assessed clinical responses up to 24 weeks using conventional criteria.Results: Before treatment, metastases showed specific 99mTc-maraciclatide accumulation (mean planar T:N and T:M ratios 1.43 and 3.06; SPECT T:N and T:M ratios 3.1 and 5.19, respectively). Baseline sclerotic lesions (389-740 HU) showed lower T:M ratios (4.22 vs. 7.04, p = 0.02) than less sclerotic/lytic lesions (46-381 HU). Patients with progressive disease (PD; n = 5) showed increased planar T:N and T:M ratios (0.29 and 12.1%, respectively) and SPECT T:N and T:M ratios (11.9 and 20.2%, respectively). Patients without progression showed decreased planar T:N and T:M ratios (0.27 and −8.0%, p = 1.0 and 0.044, respectively) and SPECT T:N and T:M ratios (−21.9, and −27.2%, p = 0.3 and 0.036, respectively). The percentage change in CT HU was inversely correlated with the percentage change in SPECT T:M ratios (r = −0.59, p = 0.006).Conclusions: 99mTc-maraciclatide accumulates in PCa bone metastases in keeping with increased αvβ3 integrin expression. Greater activity in metastases with lower CT density suggests that uptake is related to osteoclast activity. Changes in planar and SPECT T:M ratios after 12 weeks of treatment differed between patients with and without PD and 99mTc-maraciclatide imaging may be a potential method for assessing early response. [ABSTRACT FROM AUTHOR]

Introduction: The αvβ3 integrin, which is expressed by angiogenic epithelium and some tumor cells, is an attractive target for the development of both imaging agents and therapeutics. While optimal implementation of αvβ3-targeted therapeutics will require a priori identification of the presence of the target, the clinical evaluation of these compounds has typically not included parallel studies with αvβ3-targeted diagnostics. This is at least partly due to the relatively limited availability of PET radiopharmaceuticals in comparison to those labeled with 99mTc. In an effort to begin to address this limitation, we evaluated the tumor uptake of 99mTc-NC100692, a cyclic RGD peptide that binds to αvβ3 with ~1-nM affinity, in an αvβ3-positive tumor model as well as its in vivo specificity. Methods: MicroSPECT imaging was used to assess the ability of cilengitide, a therapeutic with high affinity for αvβ3, to block and displace 99mTc-NC100692 in an orthotopic U87 glioma tumor. The specificity of 99mTc-NC100692 was quantitatively evaluated in mice bearing subcutaneous U87MG tumors, by comparison of the biodistribution of 99mTc-NC100692 with that of the non-specific structural analogue 99mTc-AH-111744 and by blocking uptake of 99mTc-NC100692 with excess unlabeled NC100692. Results: MicroSPECT imaging studies demonstrated that uptake of 99mTc-NC100692 in the intracranial tumor model was both blocked and displaced by the αvβ3-targeted therapeutic cilengitide. Biodistribution studies provided quantitative confirmation of these imaging results. Tumor uptake of 99mTc-NC100692 at 1h post-injection was 2.8±0.7% ID/g compared to 0.38±0.1% ID/g for 99mTc-AH-111744 (p <0.001). Blocking 99mTc-NC100692 uptake by pre-injecting the mice with excess unlabeled NC100692 reduced tumor uptake by approximately five-fold, to 0.68±0.3% ID/g (p =0.01). Conclusion: These results confirm that 99mTc-NC100692 does, in fact, target the αvβ3 integrin and may, therefore, be useful in identifying patients prior to anti-αvβ3 therapy as well as monitoring the response of these patients to therapy. [ABSTRACT FROM AUTHOR]

19-Norandrosterone (19NA) is the preferred urinary target compound to identify doping with nandrolone or related 19-norsteroids. At concentrations between 2.5 and 15 ng/mL, isotope ratio mass spectrometry (IRMS) is required to establish exogenous origin of urinary 19NA. An absolute difference of 3‰ between urinary 19NA and an endogenous reference compound (ERC) constitutes a finding for exogenous origin of 19NA. Over the last 3 years, 77 samples containing urinary 19NA between 2.5 and 15 ng/mL were analyzed at our laboratory. The measured δ 13 C values for 19NA ranged from -29.5‰ to -16.8‰. In comparison, the δ 13 C values for the corresponding urinary ERCs ranged from -22.4‰ to -16.2‰. Due to the considerable overlap in values between the target compound and the natural range of urinary ERCs, it can be challenging to distinguish between endogenous and exogenous origins of urinary 19NA. In addition, it is well known that consumption of offal from non-castrated pigs can produce 19NA in urine. To determine whether this could cause a positive IRMS finding under the current IRMS positivity criteria, meat from non-castrated boars fed a mixture of corn and soy was consumed by 13 volunteers. Two volunteers produced 19NA findings above 2.5 ng/mL, and the measured isotope values, while inconsistent with documented 19-norsteroid preparations, did meet IRMS positivity criteria. However, these increases in 19NA urinary concentrations were short-lived due to rapid elimination. Timely follow-up collections may help support a claim for dietary exposure when low urinary concentrations of 19NA with pseudo-endogenous isotope values are observed., (© 2023 John Wiley & Sons Ltd.)

Unlabelled: Arginine-glycine-aspartate (RGD)-binding α(V)β(3)-integrin and α(V)β(5)-integrin play key roles in tumor angiogenesis. We examined an (18)F-labeled small peptide (fluciclatide [United States Adopted Name (ASAN)-approved, International Nonproprietary Name (INN)-proposed name], previously referred to as AH111585) containing an RGD sequence. Fluciclatide binds with a high (nM) affinity to α(V)β(3)-integrin and α(V)β(5)-integrin, which are highly expressed on tumors and the tumor neovasculature. In this study, (18)F-fluciclatide was used to examine the response of human glioblastoma xenografts to treatment with the antiangiogenic agent sunitinib., Methods: U87-MG tumor uptake of (18)F-fluciclatide was determined by small-animal PET after longitudinal administration of the antiangiogenic agent sunitinib (a 2-wk dosing regimen). Tumor sizes were measured throughout the study, and tumor volumes were calculated. Tumor microvessel density (MVD) after therapy was also analyzed., Results: Dynamic small-animal PET of (18)F-fluciclatide uptake after administration of the clinically relevant antiangiogenic agent sunitinib revealed a reduction in the tumor uptake of (18)F-fluciclatide compared with that in vehicle-treated controls over the 2-wk dosing regimen. Skeletal muscle, used as a reference tissue, showed equivalent (18)F-fluciclatide uptake in both therapy and control groups. A reduction in tumor MVD was also observed after treatment with the antiangiogenic agent. No significant changes in tumor volume were observed in the 2 groups., Conclusion: The data demonstrated that (18)F-fluciclatide detected changes in tumor uptake after acute antiangiogenic therapy markedly earlier than any significant volumetric changes were observable. These results suggest that this imaging agent may provide clinically important information for guiding patient care and monitoring the response to antiangiogenic therapy.

Unlabelled: Despite the recent development of various radiolabeled Arg-Gly-Asp (RGD) peptides for imaging the alphavbeta3 integrin receptor, relatively little attention has been focused on the ability of these radiotracers to monitor changes in tumor vascularity after antitumor therapies. This study describes the favorable in vivo kinetics and tumor-targeting properties of 18F-AH111585, a novel 18F-RGD peptide, and its ability to monitor tumor vascularity noninvasively., Methods: Mice bearing Lewis lung carcinoma (LLC) tumors or Calu-6 non-small cell lung tumor xenografts were used for in vivo biodistribution and small-animal PET imaging studies. In addition, some animals were treated with either low-dose paclitaxel or the vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor ZD4190. Tumor uptake of 18F-AH111585 and microvessel density were then assessed., Results: Biodistribution of 18F-AH111585 demonstrated rapid clearance from the blood and key background organs and good tumor accumulation, with 1.5 percentage injected dose per gram (%ID/g) present at 2 h after injection in LLC tumors. Small-animal PET imaging of Calu-6 tumors allowed visualization of tumors above background tissue, with mean baseline uptake of 2.2 %ID/g. Paclitaxel therapy reduced the microvessel density in LLC tumor-bearing mice and resulted in significantly reduced 18F-AH111585 tumor uptake (P<0.05). ZD4190 therapy resulted in a significant (31.8%) decrease in 18F-AH111585 uptake in Calu-6 tumors, compared with the vehicle control-treated Calu-6 tumors, which had a 26.9% increase in 18F-AH111585 uptake over the same period (P<0.01)., Conclusion: 18F-AH111585 is a promising 18F-labeled RGD tracer that offers a new approach to noninvasively image tumor vasculature. This tracer may reveal important information in the assessment of the impact of antitumor therapies, in particular those that predominantly target tumor blood vessels.