Chemical compound
Clinafloxacin
is an
investigational
fluoroquinolone
antibiotic
. Despite its promising antibiotic activity, the clinical development of clinafloxacin has been hampered by its risk for inducing serious
side effects
.
Medical uses
[
edit
]
Clinafloxacin has not been approved for any indication. The
investigational new drug
application was withdrawn by the manufacturer in 1999, citing safety concerns.
[4]
Available forms
[
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]
Clinafloxacin is available in both oral and intravenous formulations.
[1]
Specific populations
[
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]
There is a warning against using clinafloxacin in pregnant patients, due to possible damage to the developing fetus.
[5]
Adverse effects
[
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]
The use of clinafloxacin is associated with
drug-induced light sensitivity
(phototoxicity) and
low blood sugar
.
[6]
Diarrhea
has also been reported.
[1]
The phototoxicity with clinafloxacin has been more associated with oral dosing as compared to intravenous dosing, though the studies that described this were subject to
confounding
by study site (that is, patients that received intravenous clinafloxacin were less mobile, and thereby received less sunlight exposure).
[1]
The mechanism for clinafloxacin's phototoxicity involves the
chlorine
atom at position 8. In the presence of
ultraviolet light
, the chemical structure of clinafloxacin is degraded, resulting in the formation of toxic,
reactive oxygen species
that can damage cellular structures?including
DNA
. For this reason clinafloxacin can also be classified as a
photocarcinogen
(a chemical that can cause light-induced cancer), though the risk of developing cancer in humans taking the medication is small.
[1]
The mechanism for clinafloxacin's effect on blood glucose is thought to involve stimulation of the pancreatic
beta cells
, which produce
insulin
(a hormone that lowers blood glucose levels).
[1]
The symptoms of clinafloxacin overdose are unknown.
[7]
Interactions
[
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]
Drug-drug interactions
[
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]
Clinafloxacin inhibits multiple
CYP450
drug metabolizing enzymes, especially
CYP1A2
.
[1]
Clinafloxacin has induced the accumulation of CYP1A2 substrates, including
theophylline
, at therapeutic doses.
[1]
This can also affect the metabolism of caffeine, another CYP1A2 substrate. Caffeine consumption must be limited while taking clinafloxacin to prevent caffeine accumulation and overdose.
[2]
There is also a known interaction of clinafloxacin with
phenytoin
, resulting in a decrease in the clearance of phenytoin from the body.
[1]
The increase in INR seen in patients taking both clinafloxacin and the
anticoagulant
warfarin
has yet to be fully elucidated.
[1]
Food-drug interactions
[
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]
There are no known food-drug interactions with clinafloxacin.
[2]
Pharmacology
[
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]
Mechanism of action
[
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]
Clinafloxacin's antibiotic mechanism of action, like other
fluoroquinolones
is derived from its activity against type II topoisomerases
DNA gyrase
and
topoisomerase IV
.
[5]
Clinafloxacin has been described as a
broad-spectrum antibiotic
due to its activity against
Gram-positive
and
Gram-negative bacteria
. In addition, clinafloxacin has antibiotic activity against
anaerobic bacteria
, including the
facultative anaerobe
Pseudomonas aeruginosa
.
[3]
Clinafloxacin's activity against anaerobic bacteria is higher than that of most other fluoroquinolones, including
ciprofloxacin
,
levofloxacin
, and
moxifloxacin
.
[8]
Pharmacokinetics
[
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]
The time that it takes for
serum
concentrations of clinafloxacin to reach the maximum concentration (
Cmax
) in healthy volunteers after taking a dose by mouth is 0.7 hours.
[3]
The elimination half-life in humans is 6.1 hours.
[3]
Steady state
levels of clinafloxacin are achieved in 3 days of twice daily dosing by mouth in healthy volunteers.
[1]
About half of an administered clinafloxacin dose is found unchanged in the urine, meaning that the drug is cleared from the blood stream roughly equally by
hepatic metabolism
(liver-induced degradation) and
renal elimination
(kidney-mediated removal).
[1]
Chemistry
[
edit
]
Clinafloxacin is a
fluoroquinolone
, structurally related to other fluoroquinolones like
ciprofloxacin
.
[5]
It is soluble in methanol (about 2 mg/mL at 25 °C) and water.
[9]
History
[
edit
]
In the 1990s, clinafloxacin showed promise as a novel, broad-spectrum fluoroquinolone antibiotic. However, further clinical trials raised serious concerns regarding its safety in humans, citing
dangerously low blood sugar
,
drug-induced light sensitivity
, and multiple
drug-drug interactions
.
[1]
Research
[
edit
]
Clinical trials have been done to assess its efficacy in
sepsis
and other serious and potentially life-threatening infections.
[1]
See also
[
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]
References
[
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]
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g
h
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k
l
m
n
o
Grayson ML, Crowe SM, McCarthy JS, Mills J, Mouton JW, Norrby SR, Paterson DL, Pfaller MA (2012).
Kucers' the use of antibiotics a clinical review of antibacterial, antifungal, antiparasitic and antiviral drugs
(6th ed.). Boca Raton, FL: CRC Press. pp. 1542?1546.
ISBN
978-1444147520
.
- ^
a
b
c
d
Pranger AD, Alffenaar JW, Aarnoutse RE (2011). "Fluoroquinolones, the cornerstone of treatment of drug-resistant tuberculosis: a pharmacokinetic and pharmacodynamic approach".
Current Pharmaceutical Design
.
17
(27): 2900?30.
doi
:
10.2174/138161211797470200
.
PMID
21834759
.
- ^
a
b
c
d
Nord CE (1999). "Use of newer quinolones for the treatment of intraabdominal infections: focus on clinafloxacin".
Infection
.
27
(3): 166?72.
doi
:
10.1007/BF02561522
.
PMID
10378126
.
S2CID
32251826
.
- ^
"W-L withdraws clinafloxacin NDA"
.
thepharmaletter.com
. The Pharma Letter
. Retrieved
14 September
2017
.
- ^
a
b
c
"Clinafloxacin"
.
PubChem
. U.S. National Library of Medicine
. Retrieved
13 September
2017
.
- ^
Rubinstein E (2001). "History of quinolones and their side effects".
Chemotherapy
. 47 Suppl 3 (3): 3?8, discussion 44?8.
doi
:
10.1159/000057838
.
PMID
11549783
.
S2CID
21890070
.
- ^
"In case of emergency/overdose"
.
clinafloxacin.com
. Archived from
the original
on 12 April 2016
. Retrieved
13 September
2017
.
- ^
Appelbaum PC (1999). "Quinolone activity against anaerobes".
Drugs
.
58
(Suppl 2): 60?4.
doi
:
10.2165/00003495-199958002-00012
.
PMID
10553708
.
S2CID
9396114
.
- ^
"Clinafloxacin Hydrochloride (CAS 105956-99-8)"
.
scbt.com
. Santa Cruz Biotechnology, Inc
. Retrieved
13 September
2017
.