| Current
Clinical Pharmacology
ISSN: 1574-8847
Current Clinical
Pharmacology
Volume 1, Number 1, January 2006
Contents
Clinical Trials are Often False Positive: A Review of Simple
Methods to Control This Problem Pp.1-4
Ton J. Cleophas and Aeilko H. Zwinderman
[Abstract] [Full
Text Article]
Pharmacokinetics and Metabolic Drug Interactions
Pp.5-20
S.E. Leucuta and L. Vlase
[Abstract] [Full
Text Article]
Recommendations for the Treatment of Hypertension in
Patients with DM: Critical Evaluation based on Clinical Trials
Pp.21-33
Giuseppe Derosa, Sibilla Salvadeo and Arrigo F.G.
Cicero
[Abstract] [Full
Text Article]
Variability in Response to Cardiovascular Drugs
Pp.35-46
Ehab S. EL Desoky, Hartmut Derendorf and Ulrich Klotz
[Abstract] [Full
Text Article]
Improving Adherence to Antipsychotic Pharmacotherapy
Pp.47-56
Prakash S. Masand and Meera Narasimhan
[Abstract] [Full
Text Article]
Current State of the Art of New Tubulin Inhibitors
in the Clinic Pp.57-70
Isa.E.L.M. Kuppens
[Abstract] [Full
Text Article]
Tirapazamine: From Bench to Clinical Trials Pp.71-79
Loredana Marcu, and Ian Olver
[Abstract] [Full
Text Article]
Pharmacometrics of Stilbenes: Seguing Towards the Clinic
Pp.81-101
Kathryn A. Roupe, Connie M. Remsberg, Jaime A. Yáñez
and Neal M. Davies
[Abstract] [Full
Text Article]
Persistent Clinical Response of Infliximab Therapy
in Patients with Refractory Rheumatoid Arthritis, over a 3-Year
Period Pp.103-108
Paraskevi V. Voulgar, Yannis Alamanos and Alexandros A.
Drosos
[Abstract] [Full
Text Article]
Pharmacokinetics and Pharmacokinetic Variability
of Heroin and its Metabolites: Review of the Literature
Pp.109-118
Elisabeth J. Rook, Alwin D.R. Huitema, Wim van den Brink,
Jan M. van Ree and Jos H. Beijnen
[Abstract] [Full
Text Article]
Clinical Pharmacogenomics of Thiopurine
S-methyltransferase Pp.119-128
Shufeng Zhou
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Clinical Trials are Often False Positive: A Review of Simple
Methods to Control This Problem
Ton J. Cleophas and Aeilko H. Zwindermanu
[Full
Text Article]
Background: Statistical hypothesis testing is much
like gambling. If, with one statistical test, your chance
of a significant result is 5%, then, after 20 tests, it will
increase to 40%. This result is based on the play of chance.
In current clinical trials, instead of a single efficacy-variable
of one treatment, multiple efficacy-variables of more than
one treatment are increasingly assessed.
Methods: The current paper reviews some methods
for reducing the problem of falsely positive results due to
multiple testing.
Results and Conclusions: These methods include (1)
the Bonferroni test, (2) the least significant difference
(LSD) test, (3) other less conservative, more rarely used
methods like Tukey’s honestly significant difference
(HSD) test, Dunnett’s test, Student-Neuman-Keuls test,
Hochberg’s adjustment, and the Hotelling Q-square test.
Alternative approaches to the problem of multiple testing
include (4) the construct of composite endpoints, (5) no adjustment
at all, but a more philosophical approach to the interpretation
of the p-values, and (6) the replacement of the traditional
5% rejection level with a 1% rejection level or less. Evidence-based
medicine is under pressure, because trials do not adequately
apply to their target populations. As long as the effects
of multiple testing are not routinely assessed in the analysis
of clinical trials, it can not be excluded as one of the mechanisms
responsible.
[Back to top]
Pharmacokinetics and Metabolic Drug Interactions
S.E. Leucuta and L. Vlase
[Full
Text Article]
Pharmacokinetics and drug metabolism play an important role
as determinants of in vivo drug action. The CYP450
enzyme family plays a determinant role in the biotransformation
of a vast number of structurally diverse drugs. Many drug
interactions are a result of the inhibition or induction of
CYP enzymes. The non-compartmental pharmacokinetic analysis
is the most used method for analyzing data from a drug interaction
study. Compartmental analysis can be also useful and sometimes
more informative than non-compartmental analysis. Many efforts
to reduce polypharmacy are important, and pharmacokinetic
tools used to study the mechanism of drug-drug interactions
may help in a better management of pharmacotherapy including
the avoidance of clinically relevant drug interactions.
[Back to top]
Recommendations for the Treatment of Hypertension in Patients
with DM: Critical Evaluation based on Clinical Trials
Giuseppe Derosa, Sibilla Salvadeo and Arrigo F.G. Cicero
[Full
Text Article]
Hypertension (blood pressure (BP) >140/90 mmHg) is a
common comorbidity of type 2 DM (DM) and a major risk factor
for macro- and microvascular complications.
To review the effectiveness of different antihypertensive
drugs in reducing BP, and diabetic complications in patients
with DM, we analysed clinical trials, reviews and reports,
published in Cochrane Library and PubMed from 1991 to 2004.
Evidences suggest that optimal control of hypertension complications
is obtained in diabetic patients when BP values are <130/80
mmHg.
Different drug classes result useful to obtain this target
BP, but their effects on different metabolic and non-metabolic
aspects have to be taken in account and a flexible approach
according to individual response to different regimens is
essential.
[Back to top]
Variability in Response to Cardiovascular Drugs
Ehab S. EL Desoky, Hartmut Derendorf and Ulrich Klotz
[Full
Text Article]
Cardiovascular drugs are characterized by wide inter-individual
variability in dose/plasma concentration/response (therapeutic
and/or toxic) relationships. Therefore, some patients achieve
good therapeutic response to their drug therapy, while others
do not. Also, some patients experience adverse effects, which
vary from mild to life-threatening. The source of variability
in patients’ response to cardiovascular drugs may be
of pharmacokinetic and/or pharmacodynamic origin. Many factors
can potentially affect both of them such as genetics, gender,
age, disease state, environmental factors like smoking and
food, possible drug-drug interactions, and ethnicity (race).
Cardiovascular pharmacogenomics is a new field that focus
on the roles of genetic polymorphisms in drug metabolizing
enzymes and drug targets in development of variable drug response.
[Back to top]
Improving Adherence to Antipsychotic Pharmacotherapy
Prakash S. Masand and Meera Narasimhan
[Full
Text Article]
Objective: To review the consequences of
nonadherence to antipsychotic pharmacotherapy in patients
with schizophrenia, as well as associated risk factors for
nonadherence and methods of improving adherence.
Methods: Review of the literature based
on a MEDLINE search on the terms schizophrenia and adherence
or compliance, limited to the English language, supplemented
by the author’s own knowledge of the topic.
Results: Nonadherence to antipsychotic therapy
is a common reason for relapse and rehospitalization of patients
with schizophrenia and thus contributes to the high cost of
treating psychoses, adverse events, and lack of insight. Comorbid
substance abuse, little family involvement, and a poor clinician-patient
relationship are among the risk factors for nonadherence.
Patients with a negative attitude towards treatment, which
can result from adverse events, are also more likely to be
nonadherent. Strategies to improve adherence include optimizing
antipsychotic therapy, minimizing adverse events, encouraging
patient participation in psychoeducational programs, treating
comorbid substance abuse disorders, involving family members
in the treatment process, and forging a close therapeutic
relationship with the patient.
Conclusions: Improving adherence is difficult
but necessary for achieving optimal treatment outcomes. Careful
selection of drug therapy, with emphasis on a drug’s
tolerability, combined with nonpharmacologic interventions,
may help decrease nonadherence in patients with schizophrenia.
[Back to top]
Current State of the Art of New Tubulin Inhibitors in the
Clinic
Isa.E.L.M. Kuppens
[Full
Text Article]
For years the microtubule stabilizing agents docetaxel and
paclitaxel belong to the most successful clinical chemotherapeutic
agents. Several attempts have been made over the years to
equal and better these drugs. Both taxanes are associated
with the notorious side effect neurotoxicity and are often
accompanied with increased drug resistance and cross resistance
with other chemotherapeutic agents. In addition their high
lipophilicity demands use of co-solvents, which are associated
with less favorable side effects such as hypersensitivity.
To prevent these disadvantages and improve the clinical application
of the taxanes several new agents have entered clinical testing.
The agents that are discussed are the drug class of the discodermolides;
XAA296A and the epothilones; BMS-247550, BMS-310705, epo906,
kos-862 and the agents ABT-751 and D-24851. Here we present
an overview of recently performed clinical studies to determine
the current state of the art of the tubulin inhibitors which
are intended to enlarge and improve the clinical use of the
taxanes docetaxel and paclitaxel.
[Back to top]
Tirapazamine: From Bench to Clinical Trials
Loredana Marcu, and Ian Olver
[Full
Text Article]
Tumour hypoxia continues to remain one of the greatest challenges
in the treatment of solid tumours. An important avenue to
follow with both radiotherapy and chemotherapy is the development
of hypoxic cytotoxins such as tirapazamine. The present review
covers the history of tirapazamine from preclinical models
to clinical trials.The biochemistry as well as the pharmacokinetics
of this bioreductive agent are presented. Laboratory data
demonstrating the enhanced effect of radiation and cisplatin
when combined with tirapazamine are also discussed. There
is considerable evidence supporting the potentiation of anti-tumour
effect of cisplatin by tirapazamine. Several clinical trials
for various tumour sites have been testing the synergistic
effect of cisplatin-tirapazamine with and without radiotherapy.
These are also reviewed in the present paper.
The current literature data on tirapazamine leaves unanswered
questions about its action and toxicity. While the current
number of phase III trials limits comprehensive conclusions
about the administration of this drug, there is a unanimous
indication that further clinical studies are warranted.
[Back to top]
Pharmacometrics of Stilbenes: Seguing Towards the Clinic
Kathryn A. Roupe, Connie M. Remsberg, Jaime A. Yáñez
and Neal M. Davies
[Full
Text Article]
Stilbenes are small molecular weight (~200-300 g/mol), naturally
occurring compounds and are found in a wide range of plant
sources, aromatherapy products, and dietary supplements. These
molecules are synthesized via the phenylpropanoid
pathway and share some structural similarities to estrogen.
Upon environmental threat, the plant host activates the phenylpropanoid
pathway and stilbene structures are produced and subsequently
secreted. Stilbenes act as natural protective agents to defend
the plant against viral and microbial attack, excessive ultraviolet
exposure, and disease. One stilbene, resveratrol, has been
extensively studied and has been shown to possess potent anti-cancer,
anti-inflammatory and anti-oxidant activities. Found primarily
in the skins of grapes, resveratrol is synthesized by
Vitis vinifera grapevines in response to fungal infection
or other environmental stressors. Considerable research showing
resveratrol to be an attractive candidate in combating a wide
variety of cancers and diseases has fueled interest in determining
the disease-fighting capabilities of other structurally similar
stilbene compounds. The purpose of this review is to describe
four such structurally similar stilbene compounds, piceatannol,
pinosylvin, rhapontigenin, and pterostilbene and detail some
current pharmaceutical research and highlight their potential
clinical applications.
[Back to top]
Persistent Clinical Response of Infliximab Therapy in Patients
with Refractory Rheumatoid Arthritis, over a 3-Year Period
Paraskevi V. Voulgar, Yannis Alamanos and Alexandros A.
Drosos
[Full
Text Article]
Infliximab, a chimeric monoclonal anti-tumor necrosis factor
alpha antibody is approved for the treatment of patients with
rheumatoid arthritis (RA) who had an inadequate response to
methotrexate (MTX) therapy. This report provides analyses
by using infliximab in combination with various disease modifying
anti-rheumatic drugs, infliximab “survival” over
a period of three years, and its effectiveness on synovial
tissue damage using magnetic resonance (MR) imaging. The study
was started in 1999 as an open label study using infliximab
in combination with cyclosporin A (CsA) in refractory RA patients
who were unable to tolerate MTX. A total of 18 RA patients
were investigated. After a year of treatment, 80% of patients
achieved the 20% American College of Rheumatology Response
criteria. Two patients dropped out; one because of an immediate
hypersensitivity reaction and the other because of the development
of pulmonary tuberculosis. In a subsequent study we investigated
infliximab “survival” over a period of 3 years.
A total of 84 RA patients were included in the study. After
3 years of therapy, 59% of patients still continued receiving
infliximab. The factor that was associated with infliximab
“survival” was the concomitant use of MTX. A total
of 28 (33%) patients discontinued this study. More specifically,
16 (19%) presented adverse drug reactions, 9 (11%) had drug
failure, and 3 (3%) were lost from follow-up. Finally, to
evaluate by MR imaging the inflammatory tissue changes in
refractory RA patients treated with infliximab, 16 patients
were examined with MR imaging of the dominant affected wrist
and hand before and one year after therapy. The volume of
the enhancing inflammatory tissue (VEIT) was evaluated. A
significant decrease of VEIT was observed in 88% of patients
after therapy. We conclude that in refractory RA patients
infliximab was proved to be efficacious and well tolerated
in combination with CsA. The clinical response of infliximab
was persistent over a 3-year period and was associated with
the concomitant use of MTX. This clinical improvement was
also associated with the reduction of inflammatory disease
tissue damage.
[Back to top]
Pharmacokinetics and Pharmacokinetic Variability of Heroin
and its Metabolites: Review of the Literature
Elisabeth J. Rook, Alwin D.R. Huitema, Wim van den Brink,
Jan M. van Ree and Jos H. Beijnen
[Full
Text Article]
This article reviews the pharmacokinetics of heroin after
intravenous, oral, intranasal, intramuscular and rectal application
and after inhalation in humans, with a special focus on heroin
maintenance therapy in heroin dependent patients. In heroin
maintenance therapy high doses pharmaceutically prepared heroin
(up to 1000 mg/day) are prescribed to chronic heroin dependents,
who do not respond to conventional interventions such as methadone
maintenance treatment. Possible drug-drug interactions with
the hydrolysis of heroin into 6-monoacetylmorphine and morphine,
the glucuronidation of morphine and interactions with drug
transporting proteins are described. Since renal and hepatic
impairment is common in the special population of heroin dependent
patients, specific attention was paid on the impact of renal
and hepatic impairment. Hepatic impairment did not seem to
have a clinically relevant effect on the pharmacokinetics
of heroin and its metabolites. However, some modest effects
of renal impairment have been noted, and therefore control
of the creatinine clearance during heroin-assisted treatment
seems recommendable.
[Back to top]
Clinical Pharmacogenomics of Thiopurine
S-methyltransferase
Shufeng Zhou
[Full
Text Article]
Thiopurine methyltransferase (TPMT) catalyzes the S-methylation
of thiopurine drugs such as 6- mercaptopurine (6-MP), thioguanine
and azathioprine (AZA). These drugs are used to treat conditions
such as acute lymphoblastic leukemia, inflammatory bowel disease,
rheumatoid arthritis, and organ transplant rejection. This
review highlights the polymorphisms of TPMT gene
and their clinical impact on the use of thiopurine drugs.
To date, there are 18 known mutational TPMT alleles.
The three main TPMT alleles, namely TPMT *2,
*3A and *3C, account for 80 – 95% of the intermediate
and low enzyme activity. The TPMT gene exhibits significant
genetic polymorphisms among all ethnic groups studied. Patients
who inherited very low levels of TPMT activity are at greatly
increased risk for thiopurineinduced toxicity such as myelosuppression,
when treated with standard doses of these drugs, while subjects
with very high activity may be undertreated. Moreover, clinical
drug interactions may occur due to TMPT induction or inhibition.
Identification of the TPMT mutant alleles allows
physicians to tailor the dosage of the thiopurine drugs to
the genotype of the patient or to use alternatives, improving
therapeutic outcome.
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