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JAC Antimicrob Resist ; 6(1): dlae015, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38328266


Objectives: Post-traumatic osteomyelitis attributed to metallo-ß-lactamase (MBL)-producing Gram-negative bacteria presents a challenging clinical scenario. Cefiderocol emerges as a viable treatment option within the limited therapeutic options available. Patient/case description: In this brief report, we present a case of a Ukrainian patient with osteomyelitis caused by multi-drug resistant Pseudomonas aeruginosa, which was successfully treated with cefiderocol, facilitated in part by outpatient parenteral antibiotic therapy (OPAT). Results and discussion: Administration of Cefiderocol via OPAT can present a safe and effective option for treatment of post-traumatic osteomyelitis with multi-drug resistant Pseudomonas aeruginosa. A possible effect on iron homeostasis of extended treatment duration with cefiderocol may be taken into consideration.

Arzneimittelforschung ; 57(9): 562-7, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17966754


Fomocaine (CAS 56583-43-6) is a basic ether-type local anaesthetic used in dermatological practice for surface anaesthesia. For many years, modifications of the fomocaine molecule have been pursued, e.g. to improve its physicochemical properties and also in view of possible new (systemic) applications, e.g. in the treatment of migraine or as antiarrhythmic. The present paper provides a survey of the investigations undertaken with all the different series of fomocaine derivatives synthesized so far with respect to their in vitro interaction capacity at the cytochrome P450 system, in vivo toxicity (LD50; paresis of the N. ischiadicus) and local anaesthetic effects (conduction anaesthesia at the N. ischiadicus; surface anaesthesia of the cornea) in rats. The main objective of this systematic comparison of the effects of all these substances was to assess possible basic structure-activity relationships.

Anestésicos Locais/química , Anestésicos Locais/farmacologia , Sistema Enzimático do Citocromo P-450/química , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Anestésicos Locais/toxicidade , Animais , Fenômenos Químicos , Físico-Química , Córnea/efeitos dos fármacos , Citocromo P-450 CYP1A1/metabolismo , Feminino , Dose Letal Mediana , Luminescência , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Condução Nervosa/efeitos dos fármacos , Neutrófilos/fisiologia , Paralisia/induzido quimicamente , Éteres Fenílicos/toxicidade , Procaína/farmacologia , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tetracaína/farmacologia
Arzneimittelforschung ; 54(5): 265-74, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15212188


Fomocaine (CAS 56583-43-8) is a local anaesthetic (LA) with good surface anaesthesia and low toxicity, monographed in the German Extra Pharmacopoeia (DAC). In previous experiments it could be shown that both fomocaine and a couple of its derivatives need further pharmaceutical investigations. Therefore, five new C-alkylmorpholine derivatives, (OW 1, OW 3, OW 5, OW 9, and OW 11) and five 2-hydroxypropyl-beta-cyclodextrin inclusion compounds of fomocaine or OE 7000, OE 9000, OL/4, and OL/40, respectively, were compared with fomocaine and/or the respective non-cyclodextrin formulations in rats. Basing on standard methods for testing of LA effects and using two methods to characterising toxicity of LA (paresis of the N. ischiadicus, LD50) it can be concluded that: a) The good surface anaesthesia caused by fomocaine is not surpassed by its alkylmorpholine derivatives OW1-11. Only OW 11 seems to induce longer lasting conductance anaesthesia; the other OW substances (1-9) are in the same range like fomocaine. The toxicity is quite comparable for fomocaine and its OW derivatives. b) Substituted cyclodextrins are often a useful help if the water solubility of compounds is insufficient. The use of these cyclodextrin inclusion compounds resulted in slightly improved LA effects of complexed fomocaine, whereas there were nearly no significant differences between OE 7000 or OE 9000 and their cyclodextrin formulations. The toxicity of the complexed fomocaine was lower compared to fomocaine whereas the toxicity of both OE 7000 and OE 9000 was the same for the original compound and their cyclodextrin formulations. Obviously the paresis of N. ischiadicus is less pronounced after administration of the inclusion compounds. c) The cyclodextrin formulations of the new meta-fomocaines (OL/4 and OL/40) are, compared to the complexed fomocaine, without practically relevant LA effect. But OL/4 complexed is even more toxic than complexed fomocaine. On the basis of the experiments done with altogether five new fomocaine derivatives and five complexed fomocaines it can be summarized that neither the new derivatives nor their inclusion compounds seem to have any therapeutic advantage compared with the known mother substance fomocaine. Only the longer lasting effect of high doses of OW 11 as conductance LA could be of practical relevance.

Anestésicos Locais/farmacologia , Anestésicos Locais/toxicidade , Ciclodextrinas/farmacologia , Ciclodextrinas/toxicidade , Éteres Fenílicos/farmacologia , Éteres Fenílicos/toxicidade , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Anestesia por Condução , Animais , Fenômenos Químicos , Química Farmacêutica , Físico-Química , Córnea/efeitos dos fármacos , Estabilidade de Medicamentos , Excipientes , Feminino , Masculino , Músculo Esquelético/efeitos dos fármacos , Paralisia/induzido quimicamente , Ratos , Ratos Wistar , Relação Estrutura-Atividade
Arzneimittelforschung ; 53(3): 221-8, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12705179


Fomocaine (CAS 56583-43-8) is a local anaesthetic (LA) with long lasting surface effect and low toxicity. Nevertheless, it is not optimal yet. Therefore, 7 newly synthesised derivatives, 4 diethanolamines (OE 6000, OE 7000, OE 8000, OE 9000) and 3 morpholines (OE 500, OE 1000, OE 5000) were compared with procaine-HCl (CAS 51-05-8) and tetracaine-HCl (CAS 136-47-0) in rats. Based on standard methods for the testing of LA effects and using two methods for characterising side effects and toxicity of LA (paresis of the N. ischiadicus, LD50) it can be concluded that: a) The very good surface anaesthesia caused by especially fomocaine and tetracaine could be stated but concerning conduction anaesthesia procaine is better qualified. b) Concerning conduction anaesthesia, diethanolamine derivatives are more potent compared to morpholine derivatives. c) Surface anaesthesia shows a different picture: the effect of fomocaine is in between. d) The paresis of the N. ischiadicus as a first sign of toxic side effects indicated that low effect is combined with short paresis. e) Compared to the LD50 of fomocaine, the toxicity of OE 500 and OE 5000 is only one half. On the basis of the experiments with fomocaine derivatives, distinct structure-activity relationships could be demonstrated for fomocaine derivatives concerning a) LA effects and b) toxicity. Altogether OE 9000 could be a promising candidate for systemic use.

Anestésicos Locais/síntese química , Etanolaminas/síntese química , Morfolinas/síntese química , Éteres Fenílicos/síntese química , Éteres Fenílicos/farmacologia , Administração Tópica , Anestesia por Condução , Anestésicos Locais/farmacologia , Anestésicos Locais/toxicidade , Animais , Fenômenos Químicos , Físico-Química , Córnea/efeitos dos fármacos , Etanolaminas/toxicidade , Masculino , Morfolinas/toxicidade , Paralisia/induzido quimicamente , Éteres Fenílicos/toxicidade , Procaína/farmacologia , Ratos , Ratos Wistar , Tetracaína/farmacologia