Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5610_Библиотеки_им_академика_М_И_Перельмана
.pdf
462 C. Ginn et al.
https://t.me/med1917
intravenous formulations. Posaconazole has been reported to cause visual hallucinations, which is related to high serum concentrations of the drug (Parkes et al.
2016). The mechanism of antifungal activity of azoles is inhibition of the cyto-
chrome P450-dependent enzyme lanosterol 14α-demethylase causing damage to the
cell membrane and death of fungal cells (Maertens
2004).
17.3.3 Rationale of Using Nano-delivery System
for Antifungal Drugs
The rationale of using nanocarriers for the delivery of antifungal drugs is to:
(i) increase solubility, (ii) reduce toxicity, and (iii) improve pharmacokinetic and
distribution to infected tissues. The problem of poor water solubility is common with
antifungal drugs, e.g. voriconazole (0.61 mg/mL) and AmB (<1 μg/mL). Intravenous
delivery of antifungal drugs is important for the treatment of critical ly ill patients
(Chatelon et al.
fungal infections (Rodrigues and Albuquerque 2018). The development of injectable
formulations of azoles and polyene antifungal drugs is hindered by their hydrophobicity and poor water solub ility.
Several nanocarriers have been investigated for parenteral delivery of antifungal
drugs for the treatment of systemic candidiasis, e.g. lipid-based nanoparticles,
liposomes, polymeric nanoparticles, nanostructured carriers, and drug-polymer conjugates/complexes. Examples of nano-delivery systems of antifungal drugs in the
clinic and pre-clinical stage are shown in Table
Lipid-based formulations have shown great success in improving pharmacokinetics and tissue distribution and reducing toxicity of antifungal drugs such as AmB
in the form of liposomes and lipid complexes (Faustino and Pinheiro
conventional formulation of AmB that is used in the clinic is Fungizone
AmB-deoxycholate; although this formulation is effective in treating systematic/
invasive candidiasis, it has a narrow therapeutic index due the drug’s ability to cause
nephrotoxicity (Laniado-Laborín and Cabrales-Vargas 2009). In the 1990s, two
lipid-based nanosized formulations of AmB (AmBisome
approved by the FDA and EM A and these are still commercially available in several
countries.
These lipid-based formulations have reduced the toxicity of AmB by selective
and controlled release of AmB from the lipid carrier to the fungal cells while
preventing interaction of AmB with the host membrane cholesterol (Adler-Moore
et al.
2019; Loo et al. 2013). There are several hypotheses by which AmB in the form
of lipid-based formulations can reach the fungal cells. Upon endocytosis of lipid
vesicles by the viscoelastic fungal cell wall, AmB can be released from the lipid
vesicle inside the cell (Walker et al.
AmB-lipid vesic le to interact directly with the fungal cell due to the lipid’s high
affinity to ergosterol (Foglia et al.
2019). Intravenous AmB is the main treatment choice for invasive
17.3.
2020). The
®
which is
®
and Amphocil® ) were
2018). It might also be possible for the
2015). Furthermore, the lipid formulation might be
17 Anti-infective Drug Nanosystems 463
https://t.me/med1917
Clinical
dose of 0.5–0.6 mg/kg daily for 7 days and then
three times a week (duration of treatment was
14 days) (Rex et al. 1994). It is used for treatment
of invasive candidiasis in critically ill patients (Rex
Clinical
is effective in treatment of:
®
2003)
et al.
IV AmBisome
2009) and (ii) neonatal
systemic candidiasis; 83% of infants were cured
(i) invasive candidiasis and candidemia in intensive
care patients (Dupont et al.
intravenously over 21 days (Juster-Reicher et al.
after receiving cumulative dose of 94 mg/kg given
is considered first-line treat-
®
2000). AmBisome
adults (Dupont et al. 2009; Queiroz-Telles et al.
ment of invasive candidiasis in paediatrics and
(10 mg/kg/week) for two weeks given
®
AmBisome
2008; Azoulay et al. 2017). Weekly high dose of
to critically ill patients have shown high efficacy
2017)
for treatment of ICU-acquired sepsis and multiple
Candida colonisation (Azoulay et al.
Clinical
2006; Burkhardt et al.
humans (von Mach et al.
It is used in the treatment of invasive candidiasis in
oral
Pre-
clinical
(continued)
2019)
2010)
C.neoformans burden in lungs, liver and spleen
more than free AmB in mice infected with
C. neoformans (Yu et al.
IV AmB-polymer complex significantly reduced the
AmB: deoxycholate (1:1) IV 79% of patients with candidemia were treated by
)
®
AmB
(Fungizone
Colloidal
system Drug Composition Route Efficacy (in vivo) Status
dispersion
Delivery
Table 17.3 Examples of nanocarrier system for delivery of antifungal drugs for treatment of systemic/invasive candidiasis
1:0.8:0.4)
Hydrogenated soy phosphatidylcholine: choles-
terol: distearoylphosphatidylglycerol: AmB (2:
)
®
(AmBisome
Liposome AmB
Voriconazole Sulphobutyl ether B-cyclodextrin IV/
Polymer
complex
(β-amino ester)
AmB Methoxy poly(ethylene glycol)-poly(lactide)-poly
464 C. Ginn et al.
https://t.me/med1917
Pre-
Pre-
clinical
effec-
rats
in
treating
more
in
is
incorporation
mg/kg
10
of
voriconazole
voriconazole
Furthermore,
liposomal
administration
unformulated
candidiasis.
that
than
voriconazole in the liposome has protected the
showed
tive
systemic
of
2018)
drug from biodegradation (Veloso et al.
Pre-
clinical
(dose 10 mg/kg on first, seventh and 14th day post-
infection) showed significant reduction on candi-
diasis in kidney and spleen in mice infected with
C. albicans. The survival rate was 80% in mice
treated with AmB nanoparticles compared to 30%
in mice receiving free AmB (Tang et al. 2014)
Pre-
clinical
in mice at concentration above 3.5 mg/kg (Halperin
clinical
2011)
(Jain et al.
kidneys and spleen in immunosuppressed mice at a
et al. 2016)
single dose of 5 mg/kg given 6 h post-infection
IV Intravenous
alpha
cholesterol,
hosphatidylcholine,
Soybean p
tocopherol
Voriconazole
IV Intravenous administration of AmB nanoparticles
succinate-b-poly(ε-caprolactone glycolide)
succinate
AmB Copolymer D-α-tocopheryl polyethylene glycol
AmB PEG IV AmB-PEG conjugates cured systemic candidiasis
IV Complete clearance of C. albicans from the lungs,
(lactic acid)
AmB Polymersomes of copolymer of PEG and poly
Liposome
Delivery
system Drug Composition Route Efficacy (in vivo) Status
Table 17.3 (continued)
Polymeric
nanoparticles
Polymeric
conjugates
Polymeric
micelle
17 Anti-infective Drug Nanosystems 465
https://t.me/med1917
phagocytised by the macrophages which then function as a reservoir of AmB and
provide both intracellular and extracellular antifungal activities of AmB (AdlerMoore et al. 2019). AmB might dissociate from the lipid and the released AmB
will kill intracellular fungi or exit the macrophages as free AmB to kill extracellular
fungi.
Other lipid-based formulations such as solid lipid nanoparticles, lipid
nanospheres, and nanostructured lipid carriers have shown promising pre-clinical
results as delivery systems of antifungal drugs (Table
structured lipid carriers containing both solid and liquid lipids in their composition
were used to encapsulate fluconazole resulting in an improvement of its activity
against Candida spp. in vitro (Kelidari et al.
Polymeric nanoparticles in the form of polymeric micelles, drug-polymer conjugates/complexes have been investigated for delivery of antifungal drugs such as
AmB and voriconazole (Table 17.3). Biodegradable and non-biodegra dable polymers such as PEG, polycaprolactone and arabinogalactan have been used to formulate AmB. Polymer complexes such as cyclodextrins complexed with voriconazole
have been used in the clinic for treatment of invasive candidiasis in critically ill
patients (von Mach et al. 2006).
Some polymeric nanoparticles have been reported to improve antifungal activity
of AmB against intracellular C. glabrata. AmB-sulphated chitosan nanoparticles and
carboxymethylated carrageenan-conjugated AmB gelatin nanoparticles showed significant reduction of intracellular candidiasis in RAW 264.7 cells infected with
C. glabrata compared to free AmB. This might indicate that these nanoparticles
are promising carriers for intracellular delivery of AmB for treatment of C. glabrata
(Sandhya et al. 2018; Aparna et al. 2018).
The targeted delivery of antifungal drugs using ligand such as glycan that can be
used to coat liposomes has been reported to significantly improve AmB efficiency in
reducing tissue candidiasis (Ambati et al. 2022). Mannose, attached to a polymeric
carrier, or in form of a polymannose carrier has been reported to target AmB to
intracellular fungi (Francis et al. 2018).
2017).
17.3). For example, nano-
17.4 Microbial Keratitis
17.4.1 Pathology
Corneal infection or microbial keratitis (MK) is a major ophthalmic public health
problem globally and is particularly common in low- and middle-income countries.
MK frequently causes blindness from dense corneal scarring or eye loss if not
treated. Various pathogens infect the cornea: bacteria, fungi, viruses and protozoa.
In temperate regions, bacterial infections predominate, although recent increases in
fungal keratitis in the UK have been reported (Ong et al.
estimated that there are more than one million cases of fungal keratitis each year
(Brown et al. 2021). In tropical regions, filamentous fungi cause about half of MK
2016). Worldwide, it is
466 C. Ginn et al.
https://t.me/med1917
(Hoffman et al. 2021). More than 100 fungal species have been reported; Fusarium
spp. and Aspergillus spp. are most frequent (Thomas and Kaliamurthy 2013; Kredics
et al. 2015). Bacterial keratitis is caused by various Gram-positive (Streptococcus
pneumoniae, Staphylococcus aureus) and Gram-negative pathogens (Pseudo monas
aeruginosa) (Lakhundi et al.
The risk factors of MK are eye trauma, contact lens wear, and an immune
compromised state. Ocular surface diseases such as dry eyes, blepharitis, recurrent
corneal erosion, trichiasis, and epithelial defects can increase the risk of microbial
keratitis (Konda et al.
protective barriers such as the conjunctival and corneal epithelium, tear film mucus
layer, natural immune system components (tear film IgA, complement components,
conjunctiva-associated lymphoid tissues) increase the risk of MK.
Once the integrity of the corneal epithelium is lost, microbes can enter the corneal
tissues and replicate in the stroma causing corneal lesions. Bacteria and fungi secrete
proteolytic enzymes such as serine proteases and toxins that damage the cornea
(Lakhundi et al.
cells in the cornea can further damage the cornea (Lakhundi et al.
matrix metalloproteinase secretion by the immune cells contributes largely to the
corneal tissue destruction (Gao et al. 2015). Progressive corneal tissue damage might
lead to perforation and eye loss if MK is not treated early.
2021; Khoo et al. 2019; Narayanan et al. 2013). Damage to the
2017). The inflammatory response to these microbes by the immune
2017).
2017). Human
17.4.2 Conventional Therapy
The goal of therapy is to eradicate the microorganism from the corneal tissues.
Fungal keratitis is treated in the clinic using topical natamycin 5% as first- line
treatment (Sharma et al. 2022). Other topical antifungal drugs that can be used are
AmB 0.15–0.3% (especially in case of yeast infection), voriconazole 1%,
itraconazole 1%, and miconazole 1%. Voriconazole 1% can be considered a superior
alternative to natamycin because it has better corneal penetration and broadspectrum activity (Sharma et al. 2022). Furthermore, voriconazole can be given as
an intrastromal injection. However, natamycin has been reported to result in better
visual acuity after infection and deliver a better prevention of corneal perforation
compared to voriconazole (Prajna et al. 2013). Patients with poor compliance or
severe cases can be given subconjunctival injections of fluconazole as an adjunct
therapy (Isipradit 2008). Natamycin is the only US-FDA approved antifungal for
treatment of fungal keratitis (Qiu et al. 2015). Other antifungal drugs are used
off-label for treatment of fungal keratitis in clinical settings.
Bacterial keratitis is treated based on the type of bacteria that has infected the
cornea, which is identified by laboratory smear test. The most commonly used
topical treatment is cefazolin 5% which is active against non-penicillinase-producing
gram-positive bacteria (Afshari et al. 2008). However, there is increased bacterial
resistance to cefazolin (Afshari et al. 2008). Topical tobramycin 0.3% and
gentamycin 0.3% are effective against gram-negative bacteria, streptococci and
17 Anti-infective Drug Nanosystems 467
https://t.me/med1917
staphylococci but not pneumococci. Topical tobramycin is approved by the US FDA
for these ocular microbial infections. Combinations of topical tobramycin and
cefazolin are commonly used for the treatment of bacterial keratitis (McDonald
et al.
2014). Topical vancomycin 5% is effective against gram-positive bacteria
including methicillin-resistant staph ylococcus aureus and is approved by the US
FDA (Romanowski et al.
ofloxacin 0.3% (US-FDA approved), levofloxacin 1.5% (US-FDA approved),
moxifloxacin 0.5% (licensed for use in the UK and off-label in the US) and
gatifloxacin 0.3% (off-label use) are used as monotherapies for the treatment of
bacterial keratitis (Egrilmez and Yildirim-Theveny
resistance to
moxifloxacin and gatifloxacin might be considered more effective than ciprofloxacin
in managing bacterial keratitis.
ciprofloxacin has been reported (Soleimani et al.
2020). Topical ciprofloxacin 0.3% (US-FDA approved),
2020). Recently an increase in
2021), therefore
17.4.3 Rationale of Using Nano-delivery Systems
for Anti-infective Drugs in MK Treatment
The main challenges for the delivery of anti-infective drugs for treatment of MK are
most of the antifungal or antibacterial drugs fail to reach the desired concentration in
the cornea and it is difficult to maintain the therapeutic dose at the corneal surface
and tissues for a sufficient period of time. Poor intraocular penetration is caused by a
high molecular weight and poor water solubility for most of these drugs,
e.g. natamycin, AmB, ketoconazole and itraconazole (Raj et al.
has better ocular penetration and high bioavailability but can cause several side
effects such as visual disturbances, colour vision disturbances, and increased sensitivity to light.
Formulating these antimicrobial drugs using nanotechnology might overcome the
problem of poor ocular penetration and might improve their bioavailability. Nanotechnologies such as nanosuspensions, polymeric nanoparticles, solid lipid
nanoparticles, liposomes, and micelles have been developed pre-clinically to
improve the ocular penetration of these drugs, retention, and bioavailability of
antimicrobial drugs used for treatment of MK (Lakhani et al.
2019; Ch et al. 2021 ; Gebreel et al. 2021). Examples of nanotherapy for the
treatment of MK, at the pre-clinical stage, are shown in Table 17.4. Nanoparticles
have a large surface area which enables them to carry a high drug load. Furthermore,
nanoparticles have a small size which facilitates their uptakes by corneal cells
and this increases their corneal permeability, allowing these nanosystems to deliver
a high drug load to the corneal tissues (Sharma and Taniguchi
nanoparticles have been used in the topical delivery of antimicrobial drugs to the
cornea (Ch et al.
2021; Gebreel et al. 2021; Shi et al. 2022; Chhonker et al. 2015)
2021). Voriconazole
2019; Khames et al.
2017). Polymeric
468 C. Ginn et al.
https://t.me/med1917
Habib et al.
(2010)
was better in case of fluconazole liposomes compared to
fluconazole alone
®
Paul et al.
RL100 Penetration of AmB nanoparticles through an ex-vivo cor-
(2013)
nea model was 50% after 24 h following topical applica-
tion, whereas negligible penetration of unformulated drug
Chhonker et al.
was observed
Shi et al. (2022)
(2015)
(0.15% w/v)
®
by 3.36-fold in comparison to Fungizone
2.04-fold and the pre-corneal residence time was improved
be more effective in treating fungal keratitis in rabbits than
voriconazole eye drop (0.1% w/v)
Khames et al.
Penetration of natamycin nanoparticles through an ex-vivo
2014)
(2019)
Chandasana
et al. (
The bioavailability of natamycin, measured by the con-
cornea was higher (~1.6-fold) than unformulated
centration of the drug in healthy rabbit tears, was higher
natamycin
®
(~6-fold) in natamycin nanoparticles compared to
Natamet
Ch et al. (2021)
Moxifloxacin nanoparticles showed increased corneal
retention (6 h) after topical application in healthy mice eyes
measured by in vivo imaging. In a P. aeruginosa mice
keratitis model, moxifloxacin nanoparticles showed ~20-
(continued)
fold less bacterial load compared to unformulated
moxifloxacin
Delivery
system Drug Composition Efficacy and corneal permeation Reference
Table 17.4 Examples of pre-clinical topical nanotherapy for treatment of fungal and bacterial keratitis
Liposomes Fluconazole Type of lipids was not disclosed Healing of corneal ulcer caused by C.albicans in rabbits
RS100 and Eudragit
®
AmB Eudragit
Polymeric
nanoparticles
AmB Chitosan and lecithin The bioavailability of AmB in the cornea was improved by
Mucoadhesive
Econazole Chitosan-conjugated cyclodextrin Topical econazole nanoparticles (0.1% w/v) were found to
Mucoadhesive
nanoparticles
nanoparticles
5)
Natamycin Palmitostearate glyceride (Precirol ATO
Solid lipid
nanoparticles
polycaprolactone
Natamycin Poly-D-glucosamine-functionalised
Polymeric
nanoparticles
polyethylene glycol copolymer
Moxifloxacin Hydroxypropyl methacrylamide and
Polymeric
nanoparticles
17 Anti-infective Drug Nanosystems 469
https://t.me/med1917
Ustündağ-Okur
Reference
Gebreel et al.
(2021)
goat cornea
using
studies
permeation
et al. (2014)
Delivery
system Drug Composition Efficacy and corneal permeation
Table 17.4 (continued)
vitro trans-corneal
showed that norfloxacin PLGA nanoparticles loaded in
HPMC hydrogel displayed ~2.7-fold higher permeation
than unformulated drug. These nanoparticles showed
In
PLGA)
hydrogel
hydroxypropyl
in
(HPMC)
loaded
nanoparticles
methylcellulose
xacin Poly(dl-lactide-coglycolide) (
Norflo
Nanoparticles
loaded in
hydrogel
promising antibacterial activity in a pseudomonas keratitis
rabbit model
keratitis model
to commercial ofloxacin eye drops in the S. aureus rabbit
corneal opacity during 7 days of treatment when compared
Ofloxacin nanoparticles (0.3%) showed faster decrease in
gosaccharide lactate
nanoparticles modified with chitosan oli-
Ofloxacin Compritol HDS and oleic acid
Lipid-based
nanoparticles
470 C. Ginn et al.
https://t.me/med1917
(Table 17.4). Cationic mucoadhesive biodegradable polymers such as chitosan,
PLGA and polycaprolactone can be used to improve the retention of antimicrobial
drugs in the cornea and their corneal penetration. Mucoadhesive polymers interact
with the mucus layer on the surface of the cornea and this increases the residence
time of drugs at cornea surface (Shi et al.
mucoadhesive polymers are the most commonly used polymeric nanoparticles for
topical ocular delivery of antimicrobial drugs.
Solid lipid nanoparticles can penetrate easily through cornea tissues because of
their lipophilic nature, small particle size, and mucoadhesive properties. Several
solid lipid nanoparticles have shown improved corneal permeation and therapeutic
efficacy with antifungal and antibacterial drugs (Khames et al.
et al. 2014) (Table 17.4). Several nanoparticles loaded in hydrogels have shown
sustained release of antifungal and antibacterial drugs to cornea tissues, leading to
improvements in their therapeutic effect (Gebreel et al.
(Table 17.4). Cell-penetrating peptides have been used to facilitate the penetration of
antifungal drugs through the corneal epithelial cell membrane. Nanoparticles of a
complex between natamycin and the cell-penetrating peptides called Tat-dimer have
been reported to enhance the corneal epithelial cell penetration of natamycin and
increase its solubility in aqueous medium resulting in an increase in its fungal
activity (Jain et al.
2015).
2022; Chhonker et al. 2015). These
2019; Ustündağ-Okur
2021; Abbas et al. 2022)
17.5 Tuberculosis
17.5.1 Pathology
Tuberculosis (TB) is the second leading cause of death from infectious disease after
COVID-19. The danger of tuberculosis increased in areas where co-infection with
HIV/AIDS exists. TB is spread through the generation of airborne droplets (1–5 μm)
containing the bacterium Mycobacterium Tubercul osis. These droplets can remain
suspended in the air for minutes to hours after expectoration by infected people
(Churchyard et al.
mycobacterium enters the lung alveoli. In the lung, alveolar macrophages take up the
mycobacterium and they are either destroyed or they continue to replicate
(Churchyard et al. 2017; Guinn and Rubin
depends mainly on host immunity and age. When the alveolar macrophages die, the
bacterium may spread via the lymphatic system or bloodstream to the lymph nodes,
lungs, kidneys, brain or bone. The development of the disease depends mainly on the
cell-mediated immune response that develops 2–8 weeks after infection. Activated
T-lymphocytes and macrophages form granulomas that limit the spread of the
disease (Gonzalez-Juarrero
defect in the cell-mediated immunity.
2017). Infection occurs when the droplets are inhaled and the
2017). The development of the disease
2012). The infection can be contained unless there is a
17 Anti-infective Drug Nanosystems 471
https://t.me/med1917
17.5.2 Conventional Therapy
The goal of TB treatment is to halt the progression of the disease and provide a complete
cure with no potential for relapse, and to prevent the emergence of drug resistance and
death. Drug susceptible TB is cured by a combination of rifampicin, isoniazid,
pyrazinamide, and ethambutol given daily for 2 months followed by rifampicin and
isoniazid for a further 4 months (Conde and Lapa
2011). The long period of treatment
and serious side effects reduce patient compliance; however, this period of treatment is
necessary to ensure all the pathogens are eradicated and to avoid the development of
resistance. The standard treatments for TB are summarised in Table 17.5.
17.5.3 Rationale of Using Nano-delivery Systems
for Anti-TB Drugs
The concept of using nanoparticle technology for the delivery of anti-TB drugs is for
the polymer to provide a protective coat for the drug. These drug-polymer
nanoparticles after oral or aerosol administration bind to epithelial cells and are
actively transported across the epithelial layer before being taken up by the phagocytic cells (macrophages). Alveolar macrophages can take up particles in the range
of 200 nm and up to 10 μm through non-specific surface receptors (Patel et al.
The effective particle size for delivering anti-TB drugs in the form of polymeric
nanoparticles is between 200 and 400 nm (Lim et al. 2016). Uptake of nanoparticles
and M. bacterium by macrophages occurs via endocytosis (Grotz et al.
Ligand-targeted nanoparticles are taken up by macrophages via receptor-mediated
endocytosis (Grotz et al. 2018). Once the polymeric particle is inside the lysosome,
the polymer degrades and releases the drug locally killing the intra-macrophage
pathogen after which the drug enters the bloodstream (Lim et al. 2016). Several
biodegradable polymers have been investigated for delivery of anti-TB drugs
including synthetic polymers, e.g. polylactide-co-glycolide (PLGA) and, natural
polymers, e.g. alginate and chitosan. Examples of nano-delivery systems that have
been investigated to deliver anti-TB drugs are given in Table 17.6.
2015).
2018).
Table 17.5 Conventional therapy for the treatment of TB (Mohamed-Ahmed et al. 2013a)
Drug Route Mode of action
Isoniazid Oral IM
Rifampicin Oral or
Pyrazinamide Oral Inhibits synthesis of coenzyme A which plays an important role in
Ethambutol Oral Inhibits mycobacterial arabinosyltransferases involved in the for-
or IV
IV
Inhibits synthesis of mycolic acids (essential component of mycobacterial cell wall)
Inhibits bacterial RNA synthesis
fatty acid biosynthesis
mation of arabinoglycan which is an essential component of mycobacterium cell wall
Соседние файлы в папке Библиотека им академика М.И. Перельмана