Single-Dose Pharmacokinetic Study of Ciprofloxacin and Fleroxacin in Healthy Adult Nigerian Volunteers

SummaryAbout 160¯uoroquinolones and derivatives were tested for antitrypanosomal activity in a drug sensitivity assay followed by¯uorometric evaluation. The most active quinolone compounds had IC 50 values in the range from 100 to 900 ng/ml, while several derivatives were not active at a concentration of 100 lg/ml. In a structure activity relationship study, modi®cation of the quinolones at position R1, R2, R3 and R8 did not in¯uence trypanocidal activity. An exchange of the¯uor at position 6 may contribute to an increase in activity but does not entirely control it. Pyrrolidine substituents at position R7 generally were more active than other substituents at this position. Tetracyclic quinolone derivatives were amongst the most active compounds with IC 50 values in the range of 0.3±8.8 lg/ml. The in vitro cytotoxicity on HT-29 cells was determined for active compounds with IC 50 values below 1 lg/ml. In addition, six drugs with an IC 50 below 1 lg/ml and a selectivity index of more than 10 were chosen for in vivo experiments. Dose escalation experiments with a maximum dose of 100 mg/kg/bid were performed in a mouse model without central nervous system involvement. For unknown reasons the in vitro effect of the drugs could not be con®rmed in vivo, but the class of compound remains of interest for their mode of action, the low toxicity, pharmacological properties and the availability of a large number of synthesized compounds.

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“…The registered drugs ciprofloxacin and fleroxacin have a volume of distribution of 0.4 and 2.5 l/kg (Chukwuani et al . 1998).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of quinolone derivatives for antitrypanosomal activity

Keiser

Burri

2001

Tropical Med Int Health

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“…After an administration of a single oral dose (500mg), the AUC 0-∞ observed in Brazilian subjects was 1.5 to 4-fold smaller than that observed in German, Caucasian, US American, Indonesian and Chinese subjects (135)(136)(137)(138)(139)(140). A significantly higher ciprofloxacin AUC 0-∞ has been observed in Nigerian and Chinese compared with German subjects as well when administered intravenously (139,141,142). Interethnic PK differences have not been described for levofloxacin, gatifloxacin and moxifloxacin (161,(283)(284)(285)(286)(287).…”

Section: Fluoroquinolones -Ciprofloxacin Is Moderately Lipophilic Andmentioning

confidence: 92%

Improving antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis

Tsai¹

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Sepsis is a major health issue in the Australian Indigenous population. Unfortunately, the high rates of mortality and morbidity caused by sepsis or severe sepsis in this population have not significantly reduced over recent decades. Research into the role of optimisation of antibiotic therapy for improving patient outcomes is certainly an important area of need. In other patient populations, there is increasing evidence of an improvement of clinical cure rates and survival in patients with severe sepsis when antibiotic dosing results in therapeutic concentrations, that is, achieves pharmacokinetic/pharmacodynamic (PK/PD) targets. However, numerous PK changes caused by the altered physiology associated with critical illness may reduce the likelihood of such effective dosing.Previous studies have identified a number of physiological characteristics in the Australian Indigenous population which suggest that interethnic PK differences are likely in comparison with the non-Indigenous. As most PK data of antibiotics were obtained from healthy Caucasian volunteers, whether these data can be extrapolated to the critically ill Indigenous patients requires investigation.The aims of this thesis are to describe the PK of meropenem, ceftriaxone, vancomycin and piperacillin in severely septic Indigenous patients; compare the PK with existing data from nonIndigenous patients; design optimised dosing regimens for each of the study antibiotics; and quantify the variation in renal function of critically ill Indigenous patients. This thesis consists of nine Chapters:Chapter one provides an overview of the current clinical challenges encountered in antibiotic dosing in critically ill patients. It also discusses specific physiological characteristics of Australian Indigenous patients which may lead to different PK compared with non-Indigenous comparators.Chapter two comprises of a narrative review which discusses the PK/PD factors that should be considered when prescribing antibiotics to critically ill patients. This Chapter summarises data which describe an improvement in clinical outcome when antibiotics achieve PK/PD targets. ThisChapter concludes to support an individualised approach to dosing antibiotics as opposed to the 'one dose fits all' approach that is common to clinical practice.ii Chapter three incorporates a systematic review which investigates the published data describing differences in antibiotic PK between different ethnic groups. No reports on PK in Indigenous Australians were found. The predominant data described differences in PK between the Asian and Caucasian ethnicities. Typically, Asian subjects manifested higher antibiotic concentrations for antibiotics that have significant hepatic metabolism, are substrates to p-glycoprotein or other forms of active transport and/or have high alpha-1-acid glycoprotein binding.Chapter four incorporates a study which described the renal function of critically ill Australian Indigenous patients. This study found a numerically higher incidence of augmented renal clea...

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