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Garenoxacin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
James Owen Robinson, Keryn Christiansen
Dizziness, headaches, and somnolence are the most frequently reported CNS-related side effects after quinolone administration, with an overall incidence of 1–2% (Owens and Ambrose, 2005). More severe adverse events such as agitation, delirium, psychosis, and seizures have also been reported. The incidence of these side effects varies substantially depending on the quinolone used. These effects are thought to be related to the capacity of the quinolone molecules to displace gamma-aminobutyric acid from its receptors in neurons, resulting in a general stimulating effect. The effects seem to be potentiated by the concomitant administration of anti-inflammatory drugs, for example fenbufen (Lipsky and Baker, 1999). The CNS effects of garenoxacin, because of its different chemical structure, were weaker relative to CNS effects of other quinolones in a mouse model (Nakamura et al., 2003). CNS toxicity events reported in the phase II/III trials were headaches, dizziness, insomnia, anxiety, confusion, and agitation (De Salvo et al., 2005; Kobayashi and Fujimaki, 2007; Nguyen et al., 2005; Gajjar et al., 2003; EMEA, 2007; Takagi et al., 2008). However, their incidences were similar to those of CNS toxicity events observed with the comparator drug (17.5% vs. 19.7%, respectively) (EMEA, 2007). In a postmarketing study in India conducted with 12,498 patients, CNS side effects were reported in 0.06% of cases (Hajare et al., 2015).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The failure of agents such as MarimastatTM and BatimastatTM prompted a trend away from peptidic-based compounds. For example, Bayer discovered that fenbufen, a known anti-inflammatory agent, possesses modest inhibitory activity against gelatinase-A, and a series of analogs with greater potency than fenbufen was synthesized. A number of novel non-peptidic compounds were also discovered by screening synthetic and natural product libraries. For example, metalloproteinase inhibitors are found in numerous marine organisms (e.g., fish, cephalopods, mollusks, and algae) and bacteria. Through this approach, tetracycline-type derivatives with MMP inhibitory activity and hydroxamic acid analogues structurally similar to BatimastatTM were obtained from natural product screens. However, synthetic compound libraries provided the most unique new inhibitors, and Novartis identified a novel non-peptidic inhibitor of stromelysin-1, which after further elaboration led to the orally active experimental agent CGS 27023A. X-ray crystal structures of inhibitor-MMP complexes, when they became available, were also useful in allowing a more rational approach to inhibitor design. Such studies allowed the pharmaceutical company Agouron Pharmaceuticals (later acquired by Pfizer) to design the non-peptidic hydroxamic acid–containing inhibitor, prinomastat (AG-3340). This agent reached Phase III clinical trials in non-small-cell lung cancer (NSCLC) in combination with gemcitabine; however, it did not improve the overall outcome for patients. Similarly, Roche used a structure-based approach to develop an orally active compound (RO 32-3555) which had selective inhibitory activity for collagenases rather than gelatinase-A or stromelysin-1.
A γ-cyclodextrin-based metal–organic framework (γ-CD-MOF): a review of recent advances for drug delivery application
Published in Journal of Drug Targeting, 2022
Asma Hamedi, Anastasia Anceschi, Alessia Patrucco, Mahdi Hasanzadeh
CD-MOF-1 was also used for carrying the Fenbufen. Fenbufen is a nonsteroidal anti-inflammatory, analgesic, and antipyretic agent interesting because of its high analgetic efficacy and long duration of action [48]. Liu et al. effectively used the γ-CD-MOFs for loading Fenbufen [39]. The synthesis of the γ-CD-MOFs was carried out by microwave irradiation of a water solution of γ-CD, KOH, and methanol. Modifying different processing parameters such as temperature, reaction time, and the ratio between water and methanol, it was possible to modulate the dimension of the γ-CD-MOF crystals. The Fenbufen was loaded into the γ-CD-MOFs by mixing in ethanol the MOFs with 600 mg/mL of Fenbufen solution. Using the HPLC, the adsorption of the drug was estimated and different sized γ-CD-MOF were physically characterised. The specific surface area of the γ-CD-MOF was evaluated using Langmuir model. It was found out the γ-CD-MOF with a size between 100 and 300 µm shows a high specific surface area of about 751 m2/g and a rapid and high adsorption capacity for Fenbufen (196 mg/g). The FT-IR also confirmed that Fenbufen is loaded inside the cavities of γ-CD-MOFs rather than adsorbed on the surface of the sample due to the shift or absence of the peak at 1712 cm−1 related with the C = O stretching of the free Fenbufen.