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Current
Clinical Pharmacology
ISSN: 1574-8847
Current Clinical
Pharmacology
Volume 3, Number 1, January 2008
Contents
Preclinical and Clinical Efficacy of
the Bisphosphonate Ibandronate in Cancer Treatment
Pp. 1-10
Frieder Bauss and Bengt Bergström
[Abstract]
Current Pharmacological Treatment of Pulmonary Arterial
Hypertension Pp. 11-19
Paschalis Steiropoulos, Georgia Trakada
and Demosthenes Bouros
[Abstract]
AZT: An Old Drug with New Perspectives Pp.
20-37
Gabriele D’Andrea, Fabrizia Brisdelli and Argante
Bozzi
[Abstract]
Peripheral Benzodiazepine Receptor (PBR) New Insight
in Cell Proliferation and Cell Differentiation Review
Pp. 38-45
Lorenzo Corsi, Elisa Geminiani and Mario Baraldi
[Abstract]
Diagnosis and Treatment of Paraneoplastic Neurological
Syndromes Pp. 46-50
Roberta Vitaliani, Marco Zoccarato and Bruno Giometto
[Abstract]
Clinical Pharmacology of Trastuzumab Pp.
51-55
Dominique Levêque, Luc Gigou and Jean Pierre Bergerat
[Abstract]
Enzyme Inhibition and Induction in Liver Disease
Pp. 56-69
Pietro Palatini, Sara De Martin, Paola Pegoraro and Rocco
Orlando
[Abstract]
Abstracts
[Back to top]
Preclinical and Clinical Efficacy of the Bisphosphonate Ibandronate
in Cancer Treatment
Frieder Bauss and Bengt Bergström
Bisphosphonates, like ibandronate (Bondronat®),
represent the mainstay of treatment for metastatic bone disease.
Ibandronate selectively binds to bone mineral and prevents
osteoclast-mediated skeletal destruction. This review describes
the preclinical and clinical profiles of ibandronate for treatment
of cancer metastatic to bone.
In preclinical studies ibandronate reduced metastatic processes
and tumor growth, induced tumor cell apoptosis, decreased
bone pain, and enhanced biomechanical indices. Skeletal destruction
was completely prevented with ibandronate, and this directly
correlated with histomorphometry and markers of bone turnover.
Ibandronate efficacy in combination with anti-cancer therapies
is discussed. Preclinical studies demonstrated that ibandronate
does not compromise safety, including renal health
.
Intravenous and oral ibandronate had comparable efficacy in
three Phase III clinical trials. Ibandronate achieved significant
risk reductions in the incidence of skeletal-related events
and bone pain. In additional clinical studies, ibandronate
reduced markers of bone turnover. Furthermore, loading-dose
ibandronate rapidly reduced bone pain in Phase II trials.
Adjuvant trials are ongoing. The clinical safety profile (including
a 4-year follow-up study) has demonstrated renal health is
maintained with ibandronate. Overall, ibandronate preserves
skeletal integrity, has a favorable safety profile, maintains
renal function, and can rapidly reduce and maintain bone pain
below baseline levels in patients with cancer metastatic to
bone.
[Back to top]
Current Pharmacological Treatment of Pulmonary Arterial Hypertension
Paschalis Steiropoulos, Georgia Trakada and Demosthenes
Bouros
Pulmonary arterial hypertension (PAH) is a disease characterized
by an elevation in pulmonary artery pressure that can lead
to right ventricular failure and death. Conventional treatment
is based on non-specific drugs (warfarin, oxygen, diuretics).
Pure vasodilators like calcium channel antagonists have little
or no effect on the vast majority of patients. Although there
is no cure for PAH, newer medical therapies have been shown
to improve a variety of clinically relevant end-points including
survival, functional class, exercise tolerance, haemodynamics,
echocardiographic parameters and quality of life measures.
Intravenous prostacyclin, was the first introduced drug for
treatment of PAH and remains the first-line treatment for
the most severe patients. Since then the list of approved
drugs for PAH has expanded to include prostacyclin analogues
with differing routes of administration, a dual endothelin
receptor antagonist, and a phosphodiesterase-5 inhibitor.
Novel drugs have also shown promise in experimental trials
and are likely to be added to the list of options. This article
reviews the current treatments strategies for PAH.
[Back to top]
AZT: An Old Drug with New Perspectives
Gabriele D’Andrea, Fabrizia Brisdelli and Argante
Bozzi
The science of antiviral research was well advanced when
HIV/AIDS appeared as a major new virus disease in the early
1980s. The first effective antiviral compound (AZT, azidothymidine,
zidovudine) was already among the library of compounds screened
and was promptly reported to be a specific inhibitor of retroviruses,
including HIV. Due to the pivotal role of AZT in HIV treatment,
this review summarizes the most known effects -some of which
are toxic side effects- induced by AZT a drug which is still
used in the combined therapy of HIV-infected patients. Among
the toxic side effects, a severe bone marrow toxicity manifested
as anemia, neutropenia and siderosis, and caused by inhibition
of heme and globin synthesis together with a general derangement
of iron supply, have been reported. In this regard, we proved
that while AZT and its monophosphorylated derivative AZTMP
were unable to chelate iron, the triphosphate form AZTTP displayed
a significant capacity to remove iron from transferrin. Moreover,
we have previously demonstrated that AZT-exposed K562 cells
showed an increase of transferrin receptors located on the
cell membrane without affecting their biosynthesis, but slowing
down their endocytotic pathway. Interestingly, literature
data report the impairement of glycosylation reactions by
AZT. Indeed, we have shown that AZT-treated K562 cells exhibited
a reduced sialylation of proteins and lipids, and a strong
inhibition of α,(2→
8) sialyltransferase activity while β,(1→
4)galactosyltransferase and β-galactosidase
activities were significantly increased. These latter observations
could be of clinical relevance since alterations of intracellular
and cell surface carbohydrate expression and composition,
often are associated with several diseases. However, contrarily
to previous reports by other authors on AZT as an inhibitor
of plant and bacterial toxins activity, we have demonstrated
that AZT not only did not inhibit saporin toxicity, but even
increased the cytotoxic activity of this plant toxin on K562
cells. Furthermore, the review enlightens the potential utilization
of AZT as a tool in proteomics since in the recent years several
genes responding to this drug have been identified in different
cell lines. We have shown, for the first time, an over-expression
of two proteins (PDI-A3 and sthatmin), and a full repression
of two others (HSP-60 and SOD1) in AZT-exposed K562 cells.
At present, we are investigating if the above reported alterations
are a general feature of AZT-treatment of cultured cells,
or they represent a peculiar characteristic of a specific
cell line. Finally, the paper reviews a number of novel methodologies
aimed at enhancing the AZT plasma levels and its bioavailability
in all human organs in order to improve its therapeutic efficacy
against HIV infection. These new possibilities, namely the
AZT prodrug strategy, the AZT transdermal delivery and the
targeted brain delivery, are yet not in use for humans but
they are under experimental studies.
[Back to top]
Peripheral Benzodiazepine Receptor (PBR) New Insight in Cell
Proliferation and Cell Differentiation Review
Lorenzo Corsi, Elisa Geminiani and Mario Baraldi
The peripheral benzodiazepine receptor (PBR), is an 18
kDa protein of the mammalian mitochondrial membrane and is
a highly conserved protein among the mammalian. PBR is involved
in numerous biological functions, including steroid biosynthesis,
mitochondrial oxidative phosporylation and cell proliferation.
The presence of PBR at the nuclear subcellular level has been
demonstrated in aggressive breast cancer cell line and human
glioma cells, where it seems to be involved in cell proliferation.
In our previous studies we investigated the presence of nuclear
PBR in different hepatic tumour cell lines with regard to
binding to [3H] PK 11195 and protein analysis. The results
obtained by saturation binding experiments and Scatchard analysis
of nuclear PBR density in parallel with the results on the
growth curves of the cell lines tested, indicate that the
nuclear PBR density correlates inversely with cell doubling
time. Moreover, the cell line with high nuclear PBR proliferates
in response to PBR ligands, whereas that with low nuclear
PBR does not. All these findings support the idea that PBR
could play a pivotal role in cell proliferation and this receptor
protein could be potentially important either in early diagnosis
or chemopreventive strategies against degenerative disease.
[Back to top]
Diagnosis and Treatment of Paraneoplastic Neurological Syndromes
Roberta Vitaliani, Marco Zoccarato and Bruno Giometto
Paraneoplastic neurological syndromes (PNS) are remote
effects of cancer that may involve any part of the nervous
system. Rarity hinders their diagnosis and management and
at least 60% of cases do not present a tumor at neurological
symptoms onset. An important diagnostic element is detection,
in patients’ serum or cerebrospinal fluid, of onconeuronal
antibodies which recognize antigens expressed by the nervous
system and by neoplastic cells during de-differentiation.
Their detection also implies that PNS have autoimmune origin
and that immunomodulation could be an effective treatment.
The lack of clinical trials due to the rarity of PNS makes
it hard to test the efficacy of immunomodulatory therapy,
but dividing the diseases into two groups permits preliminary
analysis. A humoral immunoresponse prevails in group one and
antibodies seem to have a pathogenetic role, indicating antibody
removal strategies. Group two are mainly PNS of the central
nervous system with autoantibodies directed against intracellular
antigens, probably involving a cell-mediated mechanism. Immunotherapy
with steroids or cytotoxic immunosuppressive agents may be
useful here. Immunomodulatory treatment is always indicated
when a tumor is not found but neurological symptoms are progressing,
since first line treatment is tumor identification and, where
possible, removal.
[Back to top]
Clinical Pharmacology of Trastuzumab
Dominique Levêque, Luc Gigou and Jean Pierre Bergerat
Trastuzumab is a monoclonal antibody that targets the
extracellular domain of HER2, a member of the epidermal growth
factor receptor (EGFR) family. Trastuzumab is currently approved
for the treatment of breast cancer overexpressing HER2, given
alone or in combination with paclitaxel or docetaxel.
Trastuzumab pharmacokinetics are characterized by a low systemic
clearance, a low volume of distribution (4l) and a very long
half-life (28 days) comparable to that of endogenous immunoglobulins
G. The elimination pathways are not yet defined and the clinical
relevance of trastuzumab kinetic variability is unknown. Whether
exposure might correlate with toxic effects or inadequate
response has not been explored. No drug-drug interactions
have been reported. This is not surprising because based on
the current knowledge, no monoclonal antibody (including trastuzumab)
has been found to interact with major molecular pharmacokinetic
determinants such enzymes, drug transporters or orphan nuclear
receptors. Dosage regimens of trastuzumab are similar either
it is used in the adjuvant setting (postoperative) or in metastatic
disease. According to the official labelling, trastuzumab
is given by intravenous perfusion at a dose based on body
weight, weekly (metastatic, adjuvant) or 3-weekly (adjuvant).
The schedule also includes a loading dose at the initiation
of the treatment. The recommended duration of treatment is
currently one year (adjuvant) or until the progression of
the disease (metastatic). Regarding the adjuvant setting,
different dosage regimens have been tested (from 9 weeks to
2 years) but the optimal duration of treatment is unknown.
The short course of trastuzumab (9 weeks) appears promising
in terms of activity, tolerance and cost but should be compared
to 1 or 2-years treatments. In addition, dosing regimens might
be optimized by integrating pharmacokinetic elements. In the
adjuvant setting, given the more favorable kinetic situation
(absence of tumor penetration), a less intense dosage regimen
might be appropriate when compared with that used in metastatic
disease. Further body weight is weakly related to trastuzumab
exposure and it is not proven that it significantly affects
clinical activity. These pharmacokinetic considerations may
support the use of fixed doses given monthly, on short periods,
for the treatment of early breast cancer.
[Back to top]
Enzyme Inhibition and Induction in Liver Disease
Pietro Palatini, Sara De Martin, Paola Pegoraro and Rocco
Orlando
This article reviews the influence of liver functional
status on pharmacokinetic interactions due to inhibition and
induction of drug-metabolizing enzymes. Recent human studies
have shown that the magnitude of inhibitory interactions caused
by the reversible CYP1A2 inhibitor fluvoxamine decreases as
liver function worsens, and virtually vanishes in patients
with more advanced hepatocellular insufficiency. This effect
of liver dysfunction is independent of the pharmacokinetic
characteristics of the CYP1A2 substrate, since it has been
observed with both high- and low-clearance drugs. It is most
probably due to reduced uptake of the inhibitory drug by the
cirrhotic liver. In order to ascertain whether this is a general
phenomenon, the following questions remain to be addressed:
1) whether the inhibition of any CYP isoform is reduced in
liver disease; 2) whether the effect of liver dysfunction
depends on the chemical nature of the inhibitory drug, since
both reduced in vivo inhibition and in vitro
uptake by the cirrhotic liver have so far been shown only
for basic drugs; 3) lastly, if similar effects can also be
observed with irreversible and quasi-irreversible inhibitors,
as their accumulation kinetics in the hepatocyte may differ
from those of a reversible inhibitor.
Although many in vivo and in vitro studies
have examined the inducibility of drug-metabolizing enzymes
in liver disease, available data are incomplete and conflicting,
since both well-preserved and severely curtailed responses
to inducing agents have been reported. The reasons for these
variable responses are most probably methodological, i.e.,
differences in the type and degree of liver dysfunction of
the animals and patients examined, and in the type and dosage
of the inducing agent used. Nonetheless, the results of those
few studies which used pathologically homogeneous animal or
patient groups suggest that, like basal enzyme expression,
drug-inducible expression is also substantially preserved
in mild to moderate liver disease, whereas it is lost in severe
hepatic dysfunction. For a definitive conclusion, further
studies are necessary which examine etiologically homogeneous
patient groups and stratify patients rigorously according
to their functional hepatic reserve. Such studies should also
examine inducers with different physicochemical properties
and acting by different mechanisms, since the expression of
both hepatic transporters and nuclear receptors may be differentially
affected by liver function impairment.
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