| Reviews
on Recent Clinical Trials
ISSN: 1574-8871
Reviews on Recent Clinical Trials
Volume 5, Number 3, September 2010
Contents
Aortic Arch Calcification and Mortality in Chronic
Hemodialysis Patients Pp. 133-137
Kosaku Nitta and Tetsuya Ogawa
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Evaluation of Self Monitoring of Blood Glucose
in Non-Insulin-Treated Diabetic Patients by Randomized Controlled
Trials: Little Bang for the Buck Pp. 138-142
Mayer B. Davidson
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Article]
Mirena Intra-Uterine System: Does it Improve Long
Term Symptoms in Women with Chronic Pelvic Pain and/or Endometriosis
after Laparoscopy? A Multicentre Randomized Controlled Trial
Pp. 143-146
Dalya Alhamdan, Tommaso Bignardi, George Hardas, Harry
Merkur and George Condous
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Article]
The Pathogenesis, Complications and Therapeutic
Strategy for Hepatitis C Virusassociated Insulin Resistance
in the Era of Anti-viral Treatment Pp. 147-157
Takumi Kawaguchi, Eitaro Taniguchi, Minoru Itou, Shuji
Sumie, Sho-ichi Yamagishi and Michio Sata
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Article]
Recent Advances in Hepatitis C Virus Treatment:
Review of HCV Protease Inhibitor Clinical Trials
Pp. 158-173
Aarthi Chary and Mark Holodniy
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Article]
Gabapentin for the Treatment of Cancer-Related
Pain Syndromes Pp. 174-178
Voichita Bar Ad
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Article]
Emerging Therapies in Relapsing-Remitting Multiple
Sclerosis Pp. 179-188
James J. Marriott and Paul W. O’Con
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Article]
Development of Inhibitors of the IGF-IR/PI3K/Akt/mTOR
pathway Pp. 189-208
Mary L. Hixon, Luisa Paccagnella, Robert Millham, Raul
Perez-Olle and Antonio Gualberto
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Article]
Erratum: Pp. 209
Abstracts
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Aortic Arch Calcification and Mortality
in Chronic Hemodialysis Patients
Kosaku Nitta and Tetsuya
Ogawa
Vascular calcification is associated with poor prognosis in
hemodialysis (HD) patients. It can be assessed with computed
tomography (CT) but simple in-office techniques may provide
useful information. We compared the results obtained with
a simple non-invasive technique with those obtained using
multi-detector CT (MDCT) for aortic arch calcification volume
(AoACV) in chronic HD patients. The aortic arch calcification
score (AoACS) estimated by chest X-ray was highly correlated
with AoACV. In another cohort study, during a follow-up period
of 4.0 years, the patients with and without AoAC, 11.3% and
6.6% of cardiovascular diseases, respectively were studied.
Kaplan-Meier analysis showed that cardiovascular mortality
was significantly greater in patients with AoAC compared with
those without it. Multivariate Cox proportional hazards analysis
found that the presence of AoAC was significantly associated
with increased cardiovascular mortality (hazard ratio, 2.556;
95% confidence interval, 1.006 to 6.490; P<0.05)
after the adjustment for age, presence of diabetes, body mass
index, diastolic blood pressure, and serum albumin level.
Finally, we found that non-progressors were significantly
younger than the progressors (p=0.0419) in changes in AoACS
(ΔAoACS).
The prescribed dose of 1α-hydroxy
vitamin D3 was significantly higher in the non-progressors
than progressors. Multiple regression analysis revealed prescribed
dose of 1α-hydroxy
vitamin D3 to be significant
independent determinant of ΔAoACS.
In conclusion, the evaluation of AoACS on chest radiography
is a very simple tool for the detection of AoAC in HD patients.
Active vitamin D therapy seems to protect patients from developing
vascular calcification in chronic HD patients.
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Evaluation of Self Monitoring of Blood Glucose in
Non-Insulin-Treated Diabetic Patients by Randomized Controlled
Trials: Little Bang for the Buck
Mayer B. Davidson
Although self monitoring of blood glucose is accepted to be
effective in lowering Hb A1c levels in insulin-treated diabetic
patients, any benefit in non-insulin-treated patients remains
controversial. Observational studies cannot answer this question
because of either patient self selection (individuals with
healthier life styles chose to perform more SMBG) or physician
self selection (patients in poorer control are asked to perform
SMBG). Only randomized controlled trials (RCTs) can provide
the answer. Of the 14 published bona fide RCTs, nine show
no benefit in lowering Hb A1c levels. In four of the five
positive ones, the SMBG group received more intensive education
and/or treatment than the control group. In the one in which
patients in both groups were followed similarly, over 500
patients were required to produce a statistically significant
difference of 0.2% favoring SMBG, the clinical significance
of which is debatable. Thus, there is scant evidence that
very expensive SMBG in non-insulin-treated patients is effective
in lowering Hb A1c levels. This lack of benefit argues for
redirecting these resources into areas of diabetes care where
strong evidence exists for improving diabetes outcomes.
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Mirena Intra-Uterine System: Does it Improve Long
Term Symptoms in Women with Chronic Pelvic Pain and/or Endometriosis
after Laparoscopy? A Multicentre Randomized Controlled Trial
Dalya Alhamdan, Tommaso Bignardi, George Hardas, Harry
Merkur and George Condous
Background: Chronic pelvic pain (CPP) is a complex clinical
scenario, which affects 15% of women. The published lite-rature
lacks a consistent definition of CPP. However according to
Vercillini et al., CPP is defined by the duration
and type of pelvic pain [1]. CPP is present if the pelvic
pain persists for more than 3 months duration and is constant
or intermittent, cyclical or noncyclical in nature. Four types
of pelvic pain have also been described and these include:
cyclical pain during menstruation (dysmenorrhoea), deep dyspareunia,
dyschezia and noncyclical pelvic pain. Therefore for the purposes
of this study, CPP will be defined by these aforementioned
types of pelvic pain and duration.
Methods: Multi-centre randomised controlled trial
comparing Mirena IUS versus expectant management
in women with CPP and/or dysmenorrhoea who undergo laparoscopic
surgery. All women aged 18 - 45 years with CPP scheduled for
la-paroscopy will be eligible for inclusion. Women with a
non-gynecological cause of pelvic pain, contraindications
to the use of Mirena IUS, previous hysterectomy, contraindications
to laparoscopy and/or general anesthesia, use of hormonal
treatment in the preceding three months, underlying gynaecological
malignancies or known ovarian cysts other than en-dometriomata
will be excluded. Importantly, all randomised women with endometriosis
noted at the time of surgery will have the disease excised
laparoscopically. Routine excision of endometriosis at laparoscopy
will be performed according to the anatomical location and
type (superficial or deep infiltrating endometriosis (DIE)).
Women will be followed for up to 24 months after laparoscopic
surgery.
Results: The primary outcome measure is improvement
of pelvic pain and/or of dysmenorrhoea post-laparoscopic surgery
for women. Assuming a 30% reduction in pain for the expectantly
managed group in order to detect a reduction in pain in the
study group of 50% with an alpha of 0.05 and a beta of 0.20,
the sample size was estimated at a minimum of 103 women per
trial arm.
Discussion: This trial will provide evidence to validate
the effectiveness or otherwise of progestogen-releasing IUS
in treating women with CPP who undergo laparoscopy surgery.
The pros and cons of both trial arms will offer guidance to
clinicians in making the right treatment choice.
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The Pathogenesis, Complications and Therapeutic Strategy
for Hepatitis C Virusassociated Insulin Resistance in the
Era of Anti-viral Treatment
Takumi Kawaguchi, Eitaro Taniguchi, Minoru Itou, Shuji
Sumie, Sho-ichi Yamagishi and Michio Sata
Recent experimental and clinical studies have shown that
chronic hepatitis C virus (HCV) infection causes insulin resistance.
Since insulin resistance decreases response to antiviral treatments,
promotes inflammatory and fibrogenic reactions and increases
a risk of hepatocellular carcinoma (HCC), amelioration of
insulin resistance may be a novel therapeutic target, which
could improve the prognosis in patients with HCV-related chronic
liver disease. Despite the increased awareness of health risk
of insulin resistance, there is no common therapeutic strategy
for HCV-associated insulin resistance. Indeed, treatments
with exogenous insulin or sulfonylureas may be rather harmful
because these treatments are associated with the development
of HCC in patients with HCV infection. Meanwhile, we, along
with others, have found distinctive treatments which improve
HCV-associated insulin resistance. Administration of branched-chain
amino acids (BCAA), especially as a late evening snack, improves
glucose metabolism by improving insulin-signal cascades in
insulin resistance patients with HCV infection. In this paper,
we discuss the pathogenesis and complications for HCV-associated
insulin resistance and further review a recent clinical therapeutic
strategy using these agents for the treatment of this devastating
disorder. We also discuss therapeutic potentialities of incretin-based
therapies, new anti-diabetic agents for HCV-associated insulin
resistance and the significance of insulin resistance in the
era of new anti-viral treatments.
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Recent Advances in Hepatitis C Virus Treatment: Review
of HCV Protease Inhibitor Clinical Trials
Aarthi Chary and Mark Holodniy
Hepatitis C virus (HCV) infection affects millions of people
world-wide, and chronic infection can result in end-stage
liver disease and hepatocellular carcinoma. Conventional therapy
to date has involved combination antiviral therapy including
alpha-interferon and ribavirin; response rates with these
drugs are variable based on both viral and host factors, such
as HCV viral load, HCV genotype, HIV co-infection, host genetic
polymorphisms (such as those in the IL28B region), and other
factors. Recent advances in HCV treatment have included pegylated
forms of alpha-interferon and, more recently, the development
of specifically targeted antiviral therapy for HCV (STAT-C)
with novel HCV protease inhibitors (PIs) for genotype 1 HCV.
Although unlikely to be administered as monotherapy due to
the potential for development of HCV PI drug resistance mutations,
results of phase II trials of two PIs in development have
recently been reported, demonstrating promising therapeutic
efficacy of HCV PIs in combination with established conventional
treatment. This review outlines the advances and the challenges
in the development of these HCV PIs as effective HCV antiviral
agents and their role in clinical practice.
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Gabapentin for the Treatment of Cancer-Related Pain
Syndromes
Voichita Bar Ad
Objectives: Gabapentin was initially developed as
an antiepileptic drug but was later discovered to be an effective
treatment of neuropathic pain. Gabapentin has been successfully
used for the treatment of multiple neuropathic pain syndromes
such as diabetic neuropathy and postherpetic neuralgia. However,
limited data exist about its efficacy for other pain syndromes.
The objective of the current review is to describe, from the
literature, the role of gabapentin for the treatment of cancer-related
pain syndromes.
Methods: Studies were identified by searching the
PubMed electronic databases. Additional review articles and
article reference lists were used to identify other studies.
Results: Recent studies showed effectiveness of gabapentin
in improving the pain control in patients with neuropathic
cancer pain, already treated with opiates. Moreover, gabapentin
appeared promising in reducing the need for high total doses
of opioids and avoiding unplanned treatment interruptions
for patients with head and neck malignancies treated with
radiotherapy or concurrent chemoradiotherapy. Furthermore,
the combination of gabapentin and morphine has been shown
to effect better pain relief at lower doses of each drug when
compared with gabapentin or morphine alone in patients with
painful diabetic neuropathy or postherpetic neuralgia. The
combination of both drugs was associated with a beneficial
effect on pain-related interference with daily activity, mood,
sleep and quality of life.
Conclusions: Given the significant benefits of gabapentin
and the combination of gabapentin with opioids for the treatment
of neuropathic pain, randomized clinical trials are needed
to establish the role of these analgesic regimens for the
treatment of neuropathic cancer pain.
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Emerging Therapies in Relapsing-Remitting Multiple
Sclerosis
James J. Marriott and Paul W. O’Con
Disease modifying therapy (DMT) first became available for
relapsing-remitting multiple sclerosis (RRMS) fifteen years
ago with the development of the moderately effective injectable
agents interferon (IFN)-β
and glatiramer acetate (GA). The subsequent licensure of mitoxantrone
(MX) and natalizumab (NZ) has allowed for better control of
refractory disease at the expense of potentially life-threatening
side effects in a minority of patients. This dichotomy between
DMT potency and safety also characterizes the next generation
of DMTs.
Five oral medications (fingolimod, cladribine, teriflunomide,
laquinimod and fumarate) are at various stages of phase III
trials and it is anticipated that at least some of these will
be on the market within the next year. The development of
oral agents would be a tremendous advance with respect to
convenience and it is anticipated that this would dramatically
increase the number of patients on therapy. In parallel with
oral therapies, powerful immunosuppressive monoclonal antibodies
(alemtuzumab, rituximab/ocrelizumab, daclizumab) are also
being evaluated.
Enthusiasm for the next generation of therapies is tempered
by safety concerns. Serious and occasionally fatal complications
have occurred with the emerging monoclonal therapies and rigorous
patient selection will be required for these agents. Moreover,
some of the oral DMTs that are most eagerly awaited by patients
have also been associated with serious side-effects in the
trials to date. It is unclear how oral agents will be incorporated
into future treatment algorithms given the need to weigh the
ease of oral administration against the relative inconvenience
but long-term safety of current first-line injectable therapies.
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Development of Inhibitors of the IGF-IR/PI3K/Akt/mTOR
pathway
Mary L. Hixon, Luisa Paccagnella, Robert Millham, Raul
Perez-Olle and Antonio Gualberto
Progress has been made towards the development of agents
targeting tyrosine kinase receptors and other molecules involved
in signalling pathways important for cell proliferation, motility,
and apoptosis. Inhibitor molecules designed to be highly specific
with the aim of decreasing toxicity have proven to be generally
well tolerated. However, the efficacy of targeted agents may
be impacted by cross-talk between pathways and downregulation
of negative feed-back loops. That is the case of the IGF-IR/PI3K/Akt/mTOR
pathway. This issue raises the question of how these targeted
agents could be combined to prevent or delay resistance without
significantly increasing toxicity. Several mTOR inhibitors
have been approved for cancer therapy, and late-stage clinical
trials of IGF-IR inhibitors are underway. The outcome of ongoing
clinical studies of IGF-IR, PI3K, Akt and mTOR inhibitors
as well as further testing of the combination of these agents
will be key for the development of therapeutic options in
a wide range of oncology indications.
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