| Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 10, Number 1, January 2009
Contents
Drug Metabolisms Associated with Human Microbiome
Guest Editor: Chun-Ming Huang
Editorial Pp. 1
[PMID:
19149507 PubMed - indexed for MEDLINE]
Association of Pharmacokinetic and Pharmacodynamic Aspects
of Linezolid with Infection Outcome Pp.
2-12
K.Z. Vardakas, I. Kioumis and M.E.
Falagas
[Abstract] [Full
text article] [PMID:
19149508 PubMed - indexed for MEDLINE]
Clinical Significance of the Pharmacokinetic and Pharmacodynamic
Characteristics of Tigecycline Pp. 13-21
M.E. Falagas, D.E. Karageorgopoulos and
G. Dimopoulos
[Abstract] [Full
text article] [PMID:
19149509 PubMed - indexed for MEDLINE]
The Gut and Intestinal Bacteria in Chronic
Heart Failure Pp. 22-28
A. Sandek, S.D. Anker and S. von
Haehling
[Abstract] [Full
text article] [PMID:
19149510 PubMed - indexed for MEDLINE]
Carbohydrate-Dependent Defense Mechanisms
Against Helicobacter pylori Infection Pp.
29-40
M. Kobayashi, H. Lee, J. Nakayama and
M. Fukuda
[Abstract] [Full
text article] [PMID:
19149511 PubMed - indexed for MEDLINE]
Non-Digestible Food Ingredients, Colonic
Microbiota and the Impact on Gut Health and Immunity: A Role
for Metabolomics Pp. 41-54
D.M. Jacobs, E. Gaudier, J. van Duynhoven
and E.E. Vaughan
[Abstract] [Full
text article] [PMID:
19149512 PubMed - indexed for MEDLINE]
The Potential of p38 MAPK Inhibitors
to Modulate Periodontal Infections Pp. 55-67
K.L. Kirkwood and C. Rossa, Jr.
[Abstract] [Full
text article] [PMID:
19149513 PubMed - indexed for MEDLINE]
The Impact of Probiotic on Gut Health
Pp. 68-78
M.C. Collado, E. Isolauri, S. Salminen and
Y. Sanz
[Abstract] [Full
text article] [PMID:
19149514 PubMed - indexed for MEDLINE]
Chemotherapy-Induced Modifications to
Gastrointestinal Microflora: Evidence and Implications of
Change Pp. 79-83
A.M. Stringer, R.J. Gibson, J.M. Bowen and
D.M.K. Keefe
[Abstract] [Full
text article] [PMID:
19149515 PubMed - indexed for MEDLINE]
The Effect of Proton Pump Inhibitors
on the Human Microbiota Pp. 84-89
B.J. Vesper, A. Jawdi, K.W. Altman, G.K.
Haines III, L. Tao and J.A. Radosevich
[Abstract] [Full
text article] [PMID:
19149516 PubMed - indexed for MEDLINE]
Vaccines and Photodynamic Therapies for
Oral Microbial-Related Diseases Pp. 90-94
P.-F. Liu, W.-H. Zhu and C.-M.
Huang
[Abstract] [Full
text article] [PMID:
19149517 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
[PMID:
19149507 PubMed - indexed for MEDLINE]
Editorial:
The human microbiome contains all of the genomes
or proteomes, of all the microorganisms present in or on the
human body [1, 2]. With increasing interest in the understanding
of the association of human microbome with diseases, this
special issue is focused specifically on diseases caused by
the alteration in human microbiome. The biological mechanisms
and pharmacokinetics of various drugs are also included. In
addition, this issue also introduces some novel modalities
or concepts for treatments of human microbome-related diseases.
Two papers, by Matthew E. Falagas and his colleagues, in this
issue exemplify the pharmacokinetic/pharmacodynamic aspects
of linezolid and tigecycline, two antibiotics for human bacterial
infections including community-acquired and nosocomial pneumonia,
skin and soft tissue infections, and infections due to vancomycin-resistant
enterococci. The paper, by Anja Sandek and coworkers, discusses
the gut and intestinal bacteria in chronic heart failure and
suggest that the gut may pose a potential target for therapeutic
interventions in patients with chronic heart failure. The
paper, by Minoru Fukuda and his coworkers, demonstrated their
recent findings of inhibition of cholesterol alpha-glucosyltransferase
by mucin-type O-glycans. The finding illustrates
that a battery of carbohydrates expressed in the stomach is
closely asso-ciated with pathogenesis and prevention of Helicobacter
pylori-related diseases. The paper, by Doris M. Jacobs
and coworkers, reviews the metabolomics studies with a focus
on microbe-host mutualism and concludes that metabolomics
holds great potential to better understand the fate of non-digestible
food ingredients on gut health and immunity.
Keith L. Kirkwood and Carlos Rossa, Jr. discuss the importance
of the p38 MAPK pathway in periodontal disease progression
and the potential therapeutic consequences of pharmacological
antagonism of this pathway in the treatment of periodontal
diseases. The paper, by Maria Carmen Collado and coworkers,
introduces new evidences support the use of probiotics in
the prevention and treatment of many human diseases including
atopic diseases, immune disorders, obesity, and diabetes.
Andrea M Stringer and his colleagues explore the potentially
vital connection between intestinal microflora and the subsequent
development of chemotherapy-induced mucositis. Benjamin J.
Vesper and his colleagues summarize current advancements in
the interactions between the proton pump inhibitors and the
natural human microbiota. In this paper of Huang Chun-Ming
Eric and his coworkers, novel modalities using vaccination
and photodynamic therapies for oral microbial-related diseases
are introduced. The advantages of novel modalities are highlighted
and compared with antimicrobial agents and traditional periodontal
surgery.
We hope you enjoy reading these papers as we did. Special
thanks must go to our reviewers for this special issue.
REFERENCES
[1] Raoult, D. Human microbiome: take-home lesson on growth
promoters? Nature, 2008, 454(7205), 690-691.
[2] Whitlock, D.R. Human microbiome: hype or false modesty?
Nature, 2008, 454(7205), 690.
Dr. Chun-Ming Huang
Department of Medicine, Division of Dermatology
University of California
San Diego, Rm2317A
3350 La Jolla Village
San Diego, CA, 92161
USA
Tel: 858-552-8585; ext. 3708
Fax: 858-642-1435
E-mail: chunming@ucsd.edu
[Back to top] [PMID:
19149508 PubMed - indexed for MEDLINE]
Association of Pharmacokinetic and Pharmacodynamic Aspects
of Linezolid with Infection Outcome
K.Z. Vardakas, I. Kioumis and M.E.
Falagas
[Full
text article]
Linezolid is the first antibiotic of a new class (oxazolidinones).
It inhibits protein synthesis by binding to the bacterial
23S ribosomal RNA of the 50S subunit, thus blocking the formation
of the functional 70S initiation complex, but it does not
inhibit peptidyl transferase. Therefore, its mechanism of
action is unique and cross resistance is unlikely to occur;
however, resistant strains have already been reported, but
the rate of resistance is low in surveillance programs. Linezolid
has a favorable pharmacokinetic profile. It is rapidly absorbed
when administered orally, and it is 100% bioavailable, thus
allowing early switch from intravenous to oral administration.
The maximum plasma concentration (range between 13.1±1.8
to 19.5±4.5
μg/ml
according to the route of administration, studied population
and dosages administered to subjects) is achieved 1-2 hours
after the first dosage. It penetrates readily to most tissues
of the human body at concentrations much higher than that
of the minimal inhibitory concentrations of the targeted pathogens.
It is metabolized by oxidation in two major inactive metabolites
and is eliminated mainly through the kidneys. Linezolid is
bacteriostatic for staphylococci and enterococci but bactericidal
for pneumococci and kills bacteria in a time-dependent fashion.
It has been studied in several randomized controlled trials
and has been approved for the treatment of patients with Gram
positive bacterial infections (community-acquired and nosocomial
pneumonia, skin and soft tissue infections, and infections
due to vancomycin-resistant enterococci) including these due
to multidrug-resistant strains. Careful and judicious use
is warranted to preserve the activity of this important antibiotic.
[Back to top] [PMID:
19149509 PubMed - indexed for MEDLINE]
Clinical Significance of the Pharmacokinetic and Pharmacodynamic
Characteristics of Tigecycline
M.E. Falagas, D.E. Karageorgopoulos and
G. Dimopoulos
[Full
text article]
Tigecycline is a novel antibacterial agent with a wide spectrum
of antimicrobial activity that includes pathogens with clinically
significant resistance patterns. The clinical effectiveness
of tigecycline has been evaluated in several non-inferiority,
phase III, randomized, double-blind, controlled clinical trials
regarding, mainly, complicated skin and skin structure infections
and complicated intra-abdominal infections. Clinical data
regarding the effectiveness of tigecycline against infections
caused by multidrug-resistant pathogens that commonly affect
severely ill patients as well as community acquired pneumonia
are favorable, yet limited. The consideration of the pharmacokinetic
and pharmacodynamic properties of tigecycline may aid in further
understanding the therapeutic role of this agent. Respectively,
the utility of tigecycline in the treatment of severe infections
involving the bloodstream has not been substantiated, particularly
regarding pathogens with borderline susceptibility. Moreover,
the fact that a relatively small proportion of the administered
tigecycline dose is excreted unchanged in the urine may compromise
the effectiveness of this agent in serious urinary tract infections.
Increas-ing the dose of tigecycline to maximize effectiveness
against severe infections appears as an appealing therapeutic
option, considering the linear pharmacokinetics exhibited
by this agent. However, gastrointestinal toxicity (nausea
and vomiting) is usually dose-limiting. Further research is
recommended on therapeutic strategies to optimize the effectiveness
and safety of tigecycline therapy in severely ill patients.
[Back to top] [PMID:
19149510 PubMed - indexed for MEDLINE]
The Gut and Intestinal Bacteria in Chronic Heart Failure
A. Sandek, S.D. Anker and S. von
Haehling
[Full
text article]
Chronic heart failure (CHF) is now recognized as a multisystem
disorder with increased sympathetic tone, hormonal derangements,
an anabolic/catabolic imbalance, endothelial dysfunction,
and systemic low-grade inflammation affecting various organ
systems. Pro-inflammatory cytokines appear to play important
roles in that context. There is increasing evidence for the
gut to have a pathophysi-ological role for both chronic inflammation
and malnutrition in CHF. Indeed, disturbed intestinal microcirculation
and barrier function in CHF seem to trigger cytokine generation,
thereby contributing to further impairment in cardiac function.
On the other hand, myocardial dysfunction can induce microcirculatory
injuries leading to a disruption in the intestinal barrier.
This amplifies the inflammatory response. Furthermore, alterations
of specific absorption functions of the intestinal mucosa
in CHF may aggravate symptoms of cachexia. The increased number
of adherent bacteria seen in patients with CHF and elevated
systemic levels of anti-lipopolysaccharide immunoglobulin
A underscore this fact. Therefore, the gut poses an interesting
target for therapeutic interventions in patients with CHF.
[Back to top] [PMID:
19149511 PubMed - indexed for MEDLINE]
Carbohydrate-Dependent Defense Mechanisms Against Helicobacter
pylori Infection
M. Kobayashi, H. Lee, J. Nakayama and
M. Fukuda
[Full
text article]
Helicobacter pylori is a Gram-negative bacterium that
infects over 50% of the world’s population. This organism
causes various gastric diseases such as chronic gastritis,
peptic ulcer, and gastric cancer. H. pylori possesses
lipopolysaccharide, which shares structural similarity to
Lewis blood group antigens in gastric mucosa. Such antigenic
mimicry could result in immune tolerance against antigens
of this pathogen. On the other hand, H. pylori colonize
gastric mucosa by utilizing adhesins, which bind Lewis blood
group antigen-related carbohydrates expressed on gastric epithelial
cells. In chronic gastritis, lymphocytes infiltrate the lamina
propria, and such infiltration is facilitated by 6-sulfo sialyl
Lewis X-capped O-glycans, peripheral lymph node addressin
(PNAd), on high endothelial venule (HEV)-like vessels. The
number of HEV-like vessels increases as chronic inflammation
progresses. Furthermore, PNAd formed on HEV-like vessels disappear
once H. pylori is eradicated. These results indicate that
PNAd plays an important role in H. pylori-associated
inflammation. H. pylori barely colonizes gland mucous cell-derived
mucin where α1,4-GlcNAc-capped
O-glycans exist. In vitro experiments show
that α1,4-GlcNAc-capped
O-glycans function as a natural antibiotic to inhibit
H. pylori growth. We recently identified cholesterol α-glucosyltransferase
(CHLαGcT)
using an expression cloning strategy and showed that this
enzyme is specifically inhibited by mucin-type O-glycans
like those present in deeper portions of the gastric mucosa.
These findings show that a battery of carbohydrates expressed
in the stomach is closely associated with pathogenesis and
also prevention of H. pylori-related diseases.
[Back to top] [PMID:
19149512 PubMed - indexed for MEDLINE]
Non-Digestible Food Ingredients, Colonic Microbiota and the
Impact on Gut Health and Immunity: A Role for Metabolomics
D.M. Jacobs, E. Gaudier, J. van Duynhoven
and E.E. Vaughan
[Full
text article]
Increasing health issues related to immune and gut function
such as inflammatory disorders, resistance to infections and
metabolic syndrome demand modern analytical approaches to
accelerate nutritional research aimed at health promotion
and disease prevention. Gut microbial-human mutualism endows
the host ‘superorganism’ with a fitness advantage
including nutritional, immune and intestinal health aspects.
The gut microbiome enlarges our genome and enhances our metabolic
potential. Dietary modulation can significantly alter the
microbiota community and metabolic activity, and consequently
impacts on nutrient bioavailability and host metabolism. Although
in an early stage, microbial metabolites generated during
colonic fermentation of food stuffs may have beneficial or
deleterious effects on intestinal health and immunity, as
summarized in this review. However, current evidence is largely
based on in vitro and animal studies while substantiation
in humans is lacking. The challenge to establish coherent
links between the bioconversion of non-digestible food ingredients,
their bioavailability and their downstream effects on the
host metabolism may be achieved by metabolomics. In this review,
metabolomics studies focusing on microbe-host mutualism have
demonstrated that metabolomics is capable of detecting and
tracking diverse microbial metabolites from different non-digestible
food ingredients, of discriminating between phenotypes with
different inherent microbiota and of potentially diagnosing
infection and gastrointestinal diseases. Integrative approaches
such as the combined analysis of the metabolome in different
biofluids together with other-omics technologies will cover
exogenous and endogenous effects and hence show promise to
generate novel hypotheses for innovative functional foods
impacting gut health and immunity.
[Back to top] [PMID:
19149513 PubMed - indexed for MEDLINE]
The Potential of p38 MAPK Inhibitors to Modulate Periodontal
Infections
K.L. Kirkwood and C. Rossa, Jr.
[Full
text article]
Periodontal disease initiation and progression occurs as a
consequence of the host immune inflammatory response to oral
pathogens. The innate and acquired immune systems are critical
for the proper immune response. LPS, an outer membrane constituent
of periodontal pathogenic bacteria, stimulates the production
of inflammatory cytokines IL-1β,
TNFα,
IL-6 and RANKL either directly or indirectly. In LPS-stimulated
cells, the induction of cytokine expression requires activation
of several signaling pathways including the p38 MAPK pathway.
This review will discuss the significance of the p38 MAPK
pathway in periodontal disease progression and the potential
therapeutic consequences of pharmacological antagonism of
this pathway in the treatment of periodontal diseases.
[Back to top] [PMID:
19149514 PubMed - indexed for MEDLINE]
The Impact of Probiotic on Gut Health
M.C. Collado, E. Isolauri, S. Salminen and
Y. Sanz
[Full
text article]
The gastrointestinal tract (GIT) microbiota plays an important
role in host health due to its involvement in nutritional,
immunologic and physiological functions. Microbial imbalances
have been associated with enhanced risk of specific diseases.
This observation has allowed the introduction of microorganisms
as probiotics which are microbes with demonstrated health
benefits in humans when ingested in foods. The mechanisms
of action include the inhibition of pathogen growth by competition
for nutritional sources and adhesion sites, secretion of antimicrobial
substances, toxin inactivation. Consequently, the primary
clinical interest in the application of probiotics has been
in the prevention and treatment of gastrointestinal infections
and antibiotic-associated diarrhea diseases. The well-characterized
immunomodulatory potential of specific probiotic strains,
beyond the effect on the composition of the microbiota, has
been be used as innovative tools to alleviate intestinal inflammation,
normalize gut mucosal dysfunction, and down-regulate hypersensitivity
reactions. Clinical efficacy of specific probiotic strains
has been demonstrated in, rotavirus’s diarrhea, antibiotic
associated diarrhea, irritable bowel syndrome and food allergies.
Further, recent clinical and nutritional studies have uncovered
the function of specific strains in energy metabolism and
thereby have opened up new angles on their exploitation.
However, as these processes are highly specific, it is important
to characterize the properties of specific probiotic strains
an in order to select the best strains or strain combinations
for the target in question. Advances have prompted increased
the interest of researchers and industry and new applications
and targets are being discovered.
[Back to top] [PMID:
19149515 PubMed - indexed for MEDLINE]
Chemotherapy-Induced Modifications to Gastrointestinal Microflora:
Evidence and Implications of Change
A.M. Stringer, R.J. Gibson, J.M. Bowen and
D.M.K. Keefe
[Full
text article]
Mucositis is a common side effect of chemotherapy which remains
poorly understood. Despite advances in the understanding of
oral and small intestinal mucositis over recent years, large
intestinal mucositis, including diarrhoea, has not been well
defined and the underlying mechanisms of the condition are
yet to be established. The majority of the literature available
concerning large intestinal mucositis is based on clinical
observations, with very little basic research existing. However,
from the little research conducted, it is likely that the
intestinal microflora play a role in the development of chemotherapy-induced
mucositis. This review will explore the potentially important
relationship between intestinal microflora and the subsequent
development of chemotherapy-induced mucositis.
[Back to top]
[PMID:
19149516 PubMed - indexed for MEDLINE]
The Effect of Proton Pump Inhibitors on the Human Microbiota
B.J. Vesper, A. Jawdi, K.W. Altman, G.K.
Haines III, L. Tao and J.A. Radosevich
[Full
text article]
Proton pump inhibitors (PPIs) are commonly used to treat acid-related
diseases, most notably gastroesophageal reflux disease. PPIs
are designed to shut down the gastric proton pump (H+/K+-ATPase)
of parietal cells, thereby raising the pH of the stomach.
While effective, a number of side effects have been associated
with PPI use. Naturally occurring bacteria, some of which
are acid-producing and contain ATPase enzymes, have also been
found within the stomach, upper gastrointestinal tract, and
oral cavity. Likewise, a number of fungi are known to inhabit
the human body; some of these fungi contain H+-ATPase
enzymes. Recent literature has suggested that PPIs may be
inadvertently affecting these bacteria and fungi in two different
ways: 1) PPIs may directly target the proton pumps of the
bacteria and fungi, and/or 2) PPIs may indirectly affect the
microenvironment of the flora via changes in pH. These unintended
interactions are exasperated by the systemic distribution
of PPIs throughout the body and may potentially lead to some
of the side effects observed with PPI use. Herein we summarize
what is currently known about the interactions between the
PPIs and the natural human microbiota.
[Back to top]
[PMID:
19149517 PubMed - indexed for MEDLINE]
Vaccines and Photodynamic Therapies for Oral Microbial-Related
Diseases
P.-F. Liu, W.-H. Zhu and C.-M.
Huang
[Full
text article]
The mouth is a favorable habitat for a great variety of bacteria.
Microbial composition of dental plaque is the usual cause
of various oral diseases in humans, including dental caries,
periodontal disease and halitosis. In general, oral antibacterial
agents such as antibiotics are commonly used to treat oral
bacterial infection. Traditional periodontal surgery is painful
and time-consuming. In addition, bacterial resistance and
toxicity of antibiotics have become a global pandemic and
unavoidable. Recently, vaccines for dental caries and periodontal
disease have been developed and applied. Moreover, the use
of photodynamic therapy has become an alternative to antibiotic
drugs. The purpose of this article is to highlight the advantages
of vaccine therapy and photodynamic therapy for oral microbial-related
diseases compared to treatments with antimicrobial agents
and traditional periodontal surgery.
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