Analysis of unknown (unlabeled/mislabeled) drug products for active pharmaceutical ingredients and related substances by an international mail facility satellite laboratory equipped with rapid screening devices.

Two chemists employed a three-device rapid screening "toolkit" consisting of a handheld Raman spectrometer, transportable mass spectrometer, and portable Fourier transform infrared (FT-IR) spectrometer at an international mail facility (IMF) satellite laboratory to examine unknown (unlabeled/mislabeled) products for the presence of active pharmaceutical ingredients (APIs). Phase I of this project previously demonstrated that this toolkit was the most effective collection of instruments for identifying APIs in product types collected at IMFs during a nationwide mail blitz and Phase II of this project previously demonstrated that results generated using the toolkit during a satellite laboratory pilot program were as reliable as those generated by a full-service library when two or more of these instruments identify an API. This study (Phase III) described the results of the satellite laboratory toolkit during production mode and encompassed the period ranging from June 2021 through December 2022. During this study, a total of 858 products were examined on-site at the IMF. The satellite laboratory yielded conclusive results for 726 (84.6%) products, which were used to support regulatory action, and identified 132 (15.4%) products that required additional full-service laboratory analyses due to inconclusive results. The satellite and full-service laboratory verified/confirmed at least one API/related substance in 617 (71.9%) products. A total of 709 APIs/related substances were found in the 617 products, and 202 of these 709 compounds were unique/different. Overall, during Phases I through III of this program, 350 different substances have been identified in products collected at IMFs.

Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI.

Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd(3+) contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd(3+) binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32.PSMA exhibits a binding affinity of 1.1 ± 0.1 µM for PSMA while the metal binding affinity is maintained at 0.9 ± 0.1 × 10(-22) M. In addition, ProCA32.PSMA exhibits r1 of 27.6 mM(-1) s(-1) and r2 of 37.9 mM(-1) s(-1) per Gd (55.2 and 75.8 mM(-1) s(-1) per molecule r1 and r2, respectively) at 1.4 T. At 7 T, ProCA32.PSMA also has r2 of 94.0 mM(-1) s(-1) per Gd (188.0 mM(-1) s(-1) per molecule) and r1 of 18.6 mM(-1) s(-1) per Gd (37.2 mM(-1) s(-1) per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T1 and T2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI.

Towards the Molecular Imaging of Prostate Cancer Biomarkers Using Protein-based MRI Contrast Agents.

Prostate cancer is the most common cancer for man with a high mortality rate due to a lack of non-invasive accurate and sensitive molecular diagnostic methods. The molecular imaging of cancer biomarkers using MRI with its spatial and temporal resolution, however, is largely limited by the lack of contrast agents with high sensitivity, targeting specificity and deep tumor penetration. In this review, we will first overview the current stage of prostate cancer diagnosis and then review prostate cancer biomarkers and related imaging techniques. Since biomarker targeting moieties are essential for molecular imaging, we will use prostate-specific membrane antigen (PSMA) as an example to discuss different methods to characterize the interaction between biomarker and targeting moieties. At the end, we will review current progress of the development of targeted protein-based MRI contrast agents (ProCAs) for prostate cancer biomarkers with improved relaxivity and targeting capability.

Postural, Bone, and Joint Disorders in Parkinson's Disease.

BACKGROUND: Stooped posture was mentioned in the original description of the characteristic features of Parkinson's disease (PD). Since then, a variety of postural, bone, and joint problems have become recognized as common aspects of the illness and deserve attention. METHODS: A Medline literature search for the period from 1970 to 2016 was performed to identify articles relevant to this topic. Keywords for the search included posture, spine, bone disorders, fractures, joint disorders, kyphosis, scoliosis, stooping, camptocormia, Pisa syndrome, frozen shoulder, anterocollis, dropped head syndrome, and pain in combination with PD. The articles were then reviewed to summarize clinical features, frequency, impact, pathophysiology, and treatment options for these conditions. RESULTS: Postural disorders (kyphoscoliosis, camptocormia, Pisa syndrome, dropped head syndrome), bone mineralization disorders (osteoporosis, bone fractures), and joint disorders (frozen shoulder, dystonia involving joints, joint pain) are often seen in association with PD. Treatment options for these conditions are varied and may include medications, physical therapy, or surgical interventions. CONCLUSIONS: Posture, bone, and joint disorders are common in patients with PD; they often produce added disability, and they may be treatable.

GRPR-targeted Protein Contrast Agents for Molecular Imaging of Receptor Expression in Cancers by MRI.

Gastrin-releasing peptide receptor (GRPR) is differentially expressed on the surfaces of various diseased cells, including prostate and lung cancer. However, monitoring temporal and spatial expression of GRPR in vivo by clinical MRI is severely hampered by the lack of contrast agents with high relaxivity, targeting capability and tumor penetration. Here, we report the development of a GRPR-targeted MRI contrast agent by grafting the GRPR targeting moiety into a scaffold protein with a designed Gd(3+) binding site (ProCA1.GRPR). In addition to its strong binding affinity for GRPR (Kd = 2.7 nM), ProCA1.GRPR has high relaxivity (r1 = 42.0 mM(-1)s(-1) at 1.5 T and 25 °C) and strong Gd(3+) selectivity over physiological metal ions. ProCA1.GRPR enables in vivo detection of GRPR expression and spatial distribution in both PC3 and H441 tumors in mice using MRI. ProCA1.GRPR is expected to have important preclinical and clinical implications for the early detection of cancer and for monitoring treatment effects.