Harmonization of United States, European Union and Canadian First-in-Human Regulatory Requirements for Radiopharmaceuticals-Is This Possible?

In recent years, several new radiotracers and radionuclide therapies have been developed. There is a renaissance in nuclear medicine and molecular imaging today, for example, in terms of the ability to image and treat neuroendocrine and prostate malignancies. In order to be able to bring a new drug product from bench to bedside and assist patients, while also ensuring patient safety, stringent regulations must be met. However, differences in regulatory requirements, often based on jurisdictional politics rather than scientific evidence, can hinder global co-operation, increase expense, and slow progress. In an effort to rise above these differences, nuclear medicine advocacy organizations, regulators, and international agencies have begun to identify commonalities in the regulations to achieve harmonization. Indeed, a more streamlined approach to radiopharmaceutical drug development across jurisdictions could be achieved through establishing harmonized requirements for pre-clinical studies and manufacturing standards. This paper provides an educational overview of the regulatory and submission requirements governing investigational radiopharmaceuticals for first-in-human radiopharmaceuticals across the European and North American continents. It is hoped that through ongoing collaboration, regulatory reform and harmonization can become a reality and speed access to the most up-to-date evidence-based patient care for all.

Antimicrobial activity of flavonoids from Piper lanceaefolium and other Colombian medicinal plants against antibiotic susceptible and resistant strains of Neisseria gonorrhoeae.

BACKGROUND: The successful treatment of Neisseria gonorrhoeae (NG) infections is increasingly problematic because of the resistance of this pathogen to multiple antimicrobial agents. This development underscores the need for new antimicrobial sources. In the current study, 21 crude methanol extracts, from 19 plants used in Colombian traditional medicine for cutaneous infections, were screened for antimicrobial activity against NG. METHODS: Extracts were screened by disc susceptibility assay. In addition, the minimum inhibitory concentrations of active compounds from P. lanceaefolium were assayed using a panel of 26 NG strains comprising 12 antibiotic-resistant phenotypes. RESULTS: In all, 71% of the crude extracts exhibited antibacterial activity against the antibiotic susceptible NG strain WHO V, whereas 10% of the extracts inhibited penicillinase-producing NG strain GC1-182. The crude extract of Piper lanceaefolium was the only extract to show significant activity without ultraviolet (UV) light activation. Preliminary screening identified 3 compounds in this plant possessing antimicrobial activity: the flavonoids 5,7-dihydroxyflavanone (pinocembrin), 2',4',6'-trihydroxychalcone (pinocembrin chalcone), and the prenylated benzoic acid derivative cyclolanceaefolic acid methyl ester. Pinocembrin and pinocembrin chalcone inhibited 100% of the NG panel at 64 µg/mL and 128 µg/mL, respectively, whereas cyclolanceaefolic acid methyl ester inhibited 44% of the strains at 128 µg/mL. CONCLUSIONS: This is the first report of the antibacterial activity of Columbian plants against NG. The activity of the 2 flavonoids, pinocembrin, and pinocembrin chalcone, toward both susceptible and resistant NG strains makes them promising candidates for further research.

Garlic natural health products exhibit variable constituent levels and antimicrobial activity against Neisseria gonorrhoeae, Staphylococcus aureus and Enterococcus faecalis.

The composition of 19 garlic natural health products (NHPs) and fresh garlic extracts were determined, as was their antibacterial activity. The 19 NHPs and 5 fresh garlic extract standards were analysed for their principal active constituents. They were also extracted for 5, 10 or 15 min in water to fresh garlic equivalents of 200 mg/mL. The extract's minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) against three indicator microorganisms (Neisseria gonorrhoeae, Staphylococcus aureus and Enterococcus faecalis) were determined by the broth microdilution method. While 47% of the aqueous garlic NHP extracts exhibited activity against N. gonorrhoeae, only 16% of the aqueous extracts inhibited S. aureus or E. faecalis at all three timepoints. Generally, products with high antimicrobial activity contained higher levels of garlic constituents with comparable activity to fresh garlic extracts, while products with marginal antibacterial activity often contained lower concentrations of constituents than their product labels indicated. Different extraction times affected antibacterial activity only against N. gonorrhoeae and tended to be correlated with levels of allicin. Thus, many extracts showed discrepancies in both composition, allicin:alliin ratio and antimicrobial activity, raising concerns as to standards of preparation and quality control for these products.