Nitroxolin [TOP]

Nitroxolin or 5-nitro-8-hydroxyquinoline, used in the treatment of acute or recurrent uncomplicated urinary tract infection, has been investigated to demonstrate direct inhibitory effect on Escherichia coli adherence to solid surfaces. First of all, influence of growth medium on bacterial adherence was studied. No relation occurs between growth media enhancing production of adhesins and the ability to adhere to solid surfaces. While bacteria are grown on minimal medium, nitroxolin (MIC/16 to MIC/4) can significantly reduce bacterial adherence to urinary catheter of uropathogenic strains of Escherichia coli AL52 and 382. Increasing the concentration of nitroxolin does not proportionally modify this decrease. When growth is realised on LB broth or agar, nitroxolin does not affect bacterial adherence of strain AL52 and higher doses (8 to 32 mg.l-1) are necessary to obtain the same inhibition of adherence of strain 382. Nitroxolin, in certain conditions, can, directly and rapidly, reduce bacterial adherence to solid surfaces.

Background: According to German AWMF S3 guideline nitroxoline is recommended as one of the first-choice antibiotics for treatment of acute uncomplicated cystitis (UC) in women. Under real-world conditions the clinical efficacy of nitroxoline should be checked in a noninterventional, prospective and multicenter study (NIS) and the prevalence of nitroxoline resistance in E. coli be monitored.

Nitroxolin

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Materials and methods: Female patients with UC treated with nitroxoline (recommended dosage 250 mg tid for 5 days) were included by urologists, general practitioners (GPs), and internists in family medicine throughout Germany from April-December 2022 and followed for 21-28 days. The diagnosis and course of therapy were judged by the Acute Cystitis Symptom Score (ACSS) questionnaire and laboratory investigations (leukocyturia etc). Separately, a nationwide resistance surveillance was performed during 2019-2020 in collaboration with 23 laboratories to collect urinary E. coli isolates and test their susceptibility to nitroxoline.

Results: Of the 316 patients with mean (SD) age of 57.2 (20.4 [median 62.5]) years who were included in the NIS, 193/248 (86.3%) in the per-protocol group and in 193/263 (81.44%) in the intention-to-treat group were clinically successful. Furthermore, 96% of the patients rated the tolerability of nitroxoline as "very good" or "good". All 272 E. coli isolates tested were susceptible to nitroxoline.

Conclusions: Nitroxoline showed very good clinical results in the NIS, and 100% of the tested E. coli urine isolates were susceptible to nitroxoline. Nitroxoline can still be recommended as one of the first-choice antibiotics for treatment of UC in women.

Urinary bactericidal kinetics for E. coli ATCC 25922 in volunteers A, B, and C, using urine samples collected 0 to 2 h after the eighth dose (a) and 4 to 6 h after the 10th dose (b) of nitroxoline at 250 mg t.i.d.

Urinary bactericidal kinetics for S. saprophyticus Ho94 in volunteers A, B, and C, using urine samples collected 0 to 2 h after the eighth dose (a) and 4 to 6 h after the 10th dose (b) of nitroxoline at 250 mg t.i.d.

Urinary bactericidal kinetics for K. pneumoniae 595 in volunteers A, B, and C, using urine samples collected 0 to 2 h after the eighth dose (a) and 4 to 6 h after the 10th dose (b) of nitroxoline at 250 mg t.i.d.

We thank R.-H. Bdeker and Christine Scheibelhut (Department of Statistics, Justus Liebig University, Giessen, Germany) for statistical calculations and Birgit Blenk, Daniela Kirchbauer, and Christin Br for technical assistance in the UIT, UBT, UBK, and MIC studies. We also thank Klaus Biemel (Pharmacelsus GmbH, Saarbruecken, Germany) for determination of urinary concentrations of nitroxoline and trimethoprim and their respective metabolites.

Obviously, this agent is still active against the vast majority of uropathogenic bacteria and in particular against strains of Escherichia coli (E. coli). Pseudomonas aeruginosa and enterococci are not really within the spectrum of nitroxoline. One has to keep in mind, however, that even among E. coli and other enterobacteriaceae there are single resistant isolates. This applies in particular to problem strains resistant to many other antibiotics.

The chelating activities of nitroxoline have also been used in an anticancer setting. Nitroxoline has been shown to be more cytotoxic to HL60, DHL-4, PANC-1, and A2780 [zh] cells lines than clioquinol and other 8-hydroxyquinoline derivatives.[3] It also demonstrated an increase in reactive oxygen species (ROS) production over controls, especially when Cu2+ was added. The ROS levels reached over 350% of the controls with addition of CuCl2. The cytotoxicity production was markedly decreased with addition of ZnCl2, indicating, based on this model, that nitroxoline is not a zinc chelator. Because the zinc chelating action of clioquinol has been associated with subacute myelo-optic neuropathy, the use of nitroxoline as a cytotoxic drug in the treatment of cancers should not exhibit neurotoxic effects in humans, and in vivo trials on tumour xenografts in mice have not yielded any negative neurodegenerative effects.

Nitroxoline has been shown to inhibit the enzymatic activity of cathepsin B.[4] Cathepsin B degrades extra-cellular membrane proteins in tumor cells, allowing them to proliferate more freely, and metastasize throughout the body. Nitroxoline was shown to be a noncompetitive, reversible inhibitor of these actions in MCF-10A neoT cells. The Ki (dissociation constant) values it demonstrates are comparable to other reversible inhibitors of cathepsin B. This indicates that it may be a candidate for further trials as an anticancer drug, especially given its history as an antimicrobial agent and its well-known pharmacokinetic profile. The mechanism of action by which nitroxoline inhibits cathepsin B may also suggest that further research of noncovalent, noncompetitive inhibitors of cathepsin B could be warranted. In fact, it was recently shown that a balance exists between the potency and the kinetics of a molecule, reflected in the molecular weight, which must be optimized in order to create the best drug for inhibition of a target enzyme.[5] For example, a certain inhibitor may have a high affinity for an enzyme, but it may prove impractical to use in a clinical setting for treatment because of its size.

Nitroxoline and its analogues have also been shown to have antiangiogenic properties.[6] For example, nitroxoline inhibits MetAP2 activity, an enzyme associated with angiogenesis, and HUVEC proliferation.[7] This is further evidence that nitroxoline would make an effective anticancer drug. With different derivatives of nitroxoline demonstrating various levels of inhibition, nitroxoline may also prove to be a novel starting point for future research into cancer treatment.

In 2018 nitroxoline was identified via a clinical metagenomic next-generation sequencing analysis as a compound that could be repurposed as an amoebicidal agent against Balamuthia mandrillaris which causes the fatal disease granulomatous amoebic encephalitis (GAE).[8]

In 2021 a patient survived an infection of Balamuthia mandrillaris after treatment with nitroxoline.[9][10] The man had been given the recommended drug therapy of pentamidine, sulfadiazine, azithromycin, fluconazole, flucytosine, and miltefosine but progressed negatively. Therefore the regime was complemented with nitroxoline which required the permission of the FDA as the drug isn't approved in the United States. The cerebral lesion shrank only one week later after the new drug was added and the man later recovered.[11]

resumo patente de inveno: "sais de adio de base de nitroxolina e usos dos mesmos". a presente inveno refere-se a novos sais de adio de base de nitroxolina com maior solubilidade e maior secreo na urina sob condies fisiolgicas. as composies farmacuticas e os processos de tratamento que utilizam as composies farmacuticas tambm so descritos. a presente inveno refere-se a novos sais de adio de base de nitroxolina que possuem maior solubilidade e estabilidade em solues aquosas quando comparados com a nitroxolina ou outros sais de nitroxolina. a presente inveno refere-se ainda a composies farmacuticas que compreendem os sais de adio de base de nitroxolina e processos de tratamento ou de preveno de doenas, distrbios e estados de sade que utilizam estas composies farmacuticas. 1/1abstract patent of invention: "nitroxoline base addition salts and uses thereof". the present invention relates to new nitroxoline base addition salts with greater solubility and greater secretion in the urine under physiological conditions. pharmaceutical compositions and treatment processes using pharmaceutical compositions are also described. the present invention relates to new nitroxoline base addition salts that have greater solubility and stability in aqueous solutions when compared to nitroxoline or other nitroxoline salts. the present invention also relates to pharmaceutical compositions comprising nitroxoline base addition salts and processes for treating or preventing diseases, disorders and health conditions using these pharmaceutical compositions. 1/1

CAMPO DA INVENO [001] A presente inveno refere-se a novos sais de adio de base de nitroxolina que possuem maior solubilidade e estabilidade em solues aquosas quando comparados nitroxolina ou outros sais de nitroxolina. A presente inveno refere-se ainda a composies farmacuticas que compreendem os sais de adio de base de nitroxolina e mtodos de tratamento ou de preveno de doenas, distrbios e estados de sade utilizando estas composies farmacuticas. ANTECEDENTES DA INVENO [002] A nitroxolina um agente antimicrobiano que foi vendido comercialmente durante um longo perodo de tempo para o tratamento de infeces do trato urinrio. Foi recentemente descoberto que a nitroxolina tambm ativa na inibio da angiognese [1] e na inibio do crescimento e da inveno de cncer [2, 3].FIELD OF THE INVENTION [001] The present invention relates to new nitroxoline base addition salts that have greater solubility and stability in aqueous solutions when compared to nitroxoline or other nitroxoline salts. The present invention also relates to pharmaceutical compositions comprising the nitroxoline base addition salts and methods of treating or preventing diseases, disorders and health conditions using these pharmaceutical compositions. BACKGROUND OF THE INVENTION [002] Nitroxoline is an antimicrobial agent that has been sold commercially over a long period of time for the treatment of urinary tract infections. It has recently been discovered that nitroxoline is also active in inhibiting angiogenesis [1] and inhibiting growth and the invention of cancer [2, 3]. 17dc91bb1f