| Current
Drug Therapy
ISSN: 1574-8855
Current Drug Therapy
Volume 2, Number 3, September 2007
Contents
Tardive Dyskinesia with Atypical Antipsychotic
Drugs Pp. 168-176
Jambur Ananth, Kartik Ananth and Aparna Keshavan
[Abstract]
The Atherogenic Dyslipidemia of Metabolic Syndrome-
Are there New Effective Therapeutic Options Beyond Statins?
Pp. 177-195
Giovanni Anfossi and Mariella Trovati
[Abstract]
Novel Peptides: An Alternative Approach for the Treatment
of Diabetes Mellitus Pp. 196-204
Rumi Ghosh, Vaidehi Thanawala and Vilasrao J. Kadam
[Abstract]
Ion Exchange Resins: A Novel Way to Solve Formulation
Problems Pp. 205-209
Kisan R. Jadhav, Meenakshi Chandra, Sushma D. Kurm and
Vilasrao J. Kadam
[Abstract]
Pharmacokinetic and Pharmacodynamic Profiles of Rapid-
Acting Artemisinins in the Antimalarial Therapy Pp.
210-223
Qigui Li, Peter J. Weina and Wilbur K. Milhous
[Abstract]
Common Therapeutic Strategies for Diabetic Retinopathy
and Glaucoma Pp. 224-232
Toshiyuki Oshitari and Sayon Roy
[Abstract]
Study on Caspase-Induced Mitochondrial Dysfunction
by Anticancer Drugs Pp. 233-235
Zhimin Tao, Matthew P. Morrow, Harvey S. Penefsky, Jerry
Goodisman and Abdul-Kader Souid
[Abstract]
Aliskiren: A Novel Renin Inhibitor for Hypertension
Pp. 236-239
Vandana Tayal and Bhupinder Singh Kalra
[Abstract]
Abstracts
[Back to top]
Tardive Dyskinesia with Atypical Antipsychotic
Drugs
Jambur Ananth, Kartik Ananth and Aparna Keshavan
Tardive dyskinesia (TD) manifests as abnormal involuntary
movements that develop gradually in patients receiving antipsychotic
medication. The clinical characteristics are a) the movements
disappear from the group of muscles engaged in a voluntary
activity, b) they can be voluntarily suppressed for a few
seconds c) during sleep they disappear and d) the most frequent
site is the bucco-oral area. Movements indistinguishable from
those of TD can also occur in several neurological disorders
as well as in patients receiving phenytoin and metoclopramide.
If the offending agents are removed, drug-induced TD improves
over time in most of the patients. Its incidence in patients
receiving typical antipsychotic drugs is 5% per year and with
atypical antipsychotic drugs 0.5-1% per year indicating that
atypical antipsychotics (AAP) drugs produce TD five to ten
times less often than typical antipsychotic drugs. While the
pathophysiology of TD is not known, D2 blocking and subsequent
dopaminergic supersensitivity, GABA deficiency and structural
changes in the brain have all been implicated. The condition
is not innocuous and can produce jerky breathing, dental problems
and even premature death. Quetiapine and clozapine have very
low affinity to D2 receptors and yet they also are known to
produce TD. Recent studies have found a high prevalence of
TD; the mild TD rate was found to be increased but severe
rates were decreased. An efficient monitoring system is needed
during atypical anti-psychotic drug treatment. Such a monitoring
system should not only focus on metabolic disturbances, but
also on the occurrence of TD.
[Back to top]
The Atherogenic Dyslipidemia of Metabolic Syndrome-
Are there New Effective Therapeutic Options Beyond Statins?
Giovanni Anfossi and Mariella Trovati
The Metabolic Syndrome is commonly associated with an atherogenic
dyslipidemia which accounts for a high risk of atherothrombosis
and cardiovascular events.
The fundamental defect of patients with the Metabolic Syndrome
is the resistance to insulin action which is involved in the
appearance of a combined dyslipidemia -i.e. hypertriglyceridemia,
low HDL cholesterol, preponderance of small dense LDL particles
and post-prandial lipidemia- owing to a reduced suppression
of lipolysis in adipose tissue which leads to higher flux
of free fatty acids to liver and increased synthesis and secretion
of VLDL particles.
Beyond the primary management which involves lifestyle intervention,
patients with the Metabolic Syndrome could be treated with
different therapeutic strategies to reduce cardiovascular
risk. The main therapeutic option is statin therapy which
provides effective decrease of LDL cholesterol levels and
is shown effective in the prevention of coronary artery events,
even though controlled studies are available only for few
molecules.
In turn, controlled trials -such as BIP, VA-HIT and FIELD-
have proposed a possible benefit from fibrate administration
in normalizing lipid profile and decrease insulin resistance
in patients with the Metabolic Syndrome which exhibit low
HDL cholesterol and hypertriglyceridemia. Other lipid modifying
strategies based on nicotinic acid or ezetimibe have recently
proposed as effective in the Metabolic Syndrome on the basis
of preliminary results and could be future options. Finally,
the simultaneous use of different drugs could provide benefits,
avoiding inappropriate combinations due to the potential hazard
of adverse drug interaction.
The present review extensively examines the most recent results
in the field of treatment of dyslipidemia in patients with
the Metabolic Syndrome, starting from the trials with statin
therapy. We consider also the role of drugs which regulate
serum lipids by different mechanisms, such as fibrates, ezetimibe,
nicotinic acid and omega3 fatty acids, on the basis of the
evidences of effectiveness and safety. Finally, we take into
account the therapeutic efficacy of new drugs, such as glita-zones
and rimonabant, whose main target is to improve the insulin
sensitivity.
[Back to top]
Novel Peptides: An Alternative Approach for the Treatment
of Diabetes Mellitus
Rumi Ghosh, Vaidehi Thanawala and Vilasrao J. Kadam
With the alarming increase in the incidence of diabetes mellitus
worldwide, there is a growing need to develop new strategies
to control hyperglycemia. Currently available treatments cause
various adverse effects and do not necessarily achieve optimal
glycemic control. Recently, peptides that may ameliorate the
symptoms of diabetes mellitus have been investigated extensively
and show great promise. Synthetic analogs of amylin and incretin
mimetics may be ideal adjuncts to diabetes therapy. Amylin
analogs significantly improve postprandial control in patients
with either type 1 or type 2 diabetes without an increased
risk of hypoglycemia or weight gain. Incretin mimetics are
a new option for patients suffering from type 2 diabetes and
are being considered as a stand-alone therapy. The present
paper reviews novel peptides as potential agents for glucose
control and prevention of the complications associated with
diabetes.
[Back to top]
Ion Exchange Resins: A Novel Way to Solve Formulation
Problems
Kisan R. Jadhav, Meenakshi Chandra, Sushma D. Kurm and
Vilasrao J. Kadam
Ion exchange resins have been used to formulate pharmaceuticals
for many years. The use of ion exchange resins as drug carrier
system has been an attractive area of research because of
its many extraordinary benefits. They have not only proved
to be safe and effective excipient but they are successfully
used for their therapeutic potential as well and are now used
in many commercial formulations throughout the world. The
present review focuses on some of the common problems faced
by the formulator and how using ion exchange resins help to
solve them.
[Back to top]
Pharmacokinetic and Pharmacodynamic Profiles of Rapid-
Acting Artemisinins in the Antimalarial Therapy
Qigui Li, Peter J. Weina and Wilbur K. Milhous
Artemisinin and its derivatives were discovered to be highly
effective antimalarial drugs, which combine potent, rapid
antimalarial activity with a wide therapeutic index and an
absence of clinically important resistance. Artemisinins as
a group are poorly efficacious at curing malaria as monotherapy.
However, this shortfall is being overcome by using oral artemisinin-based
combination therapy (ACT) and intravenous artesunate (AS)
in sequential administration with slower acting antimalarial
drugs. Pharmacokinetic and pharmacodynamic (PK/PD) evaluations
demonstrate that the rapid efficacy of artemisinins is principally
due to the drug peak concentration (Cmax),
and other pharmacokinetic parameters, such as drug exposure
level (AUC) and drug exposure time (half-life) tend to be
of minor significance. The evaluation also demonstrated that
AS is a superior in PK/PD achievements either following oral
or intravenous administration when compared to other four
artemisinin drugs. Most recently, a decrease in mortality
(34.7%) has been demonstrated in a large study using intravenous
AS, as opposed to the standard of care quinine injection.
The fast efficacy and less mortality show that current artemisinins
have great advantage over other antimalarials in ACTs for
uncomplicated malaria and in sequential therapy of AS injection
for severe and complicated malaria.
[Back to top]
Common Therapeutic Strategies for Diabetic Retinopathy
and Glaucoma
Toshiyuki Oshitari and Sayon Roy
Diabetic retinopathy and glaucoma are major diseases that
cause blindness in a high percentage of the population. However,
the precise mechanisms involved in the onset and the progression
of these diseases are still not completely known. Recent studies
have shown that there appears to be an association between
these two disease processes because the incidence of glaucoma
is higher in diabetic patients than in non-diabetic patients.
To reduce the number of patients with vision loss from these
diseases, new therapeutic strategies must be established to
prevent the development and the progression of these diseases.
In this report, we focus on the biochemical links between
diabetic retinopathy and glaucoma, viz., an overexpression
of extracellular matrix and death of retinal ganglion cells.
To establish new therapeutic strategies for both diseases,
the biochemical links between diabetic retinopathy and glaucoma
and an identification of the factors that are common to the
pathogenesis of both diseases, must be determined. In addition,
the potential use of gene therapies including antisense oligonucleotides
and small interference RNAs should be considered for both
diseases. We expect that with the advent of new therapies,
a larger number of patients with diabetic retinopathy and/or
glaucoma will be cured.
[Back to top]
Study on Caspase-Induced Mitochondrial Dysfunction
by Anticancer Drugs
Zhimin Tao, Matthew P. Morrow, Harvey S. Penefsky, Jerry
Goodisman and Abdul-Kader Souid
Apoptosis, induced in tumors by anticancer agents, is characterized
by caspase activation, impaired cellular respiration and decreased
cellular ATP. Respiration in Jurkat and HL-60 cells treated
with doxorubicin, dactinomycin or platinum drugs is measured
using a Pd(II) phosphor that monitors [O2]
in cell suspensions as a function of time. Cellular ATP is
determined using the luciferin-luciferase bioluminescence
system. Intracellular caspase activation is measured by allowing
caspases to cleave Ac-DEVD-AFC to the fluorescent AFC, which
is detected on HPLC. Comparing the ways in which respiration,
ATP level, and caspase activity vary with time points up differences
between the mechanisms of actions of doxorubicin, dactinomycin
and the platinum compounds. These methods accurately determine
the sensitivity of tumors to anticancer drugs.
[Back to top]
Aliskiren: A Novel Renin Inhibitor for Hypertension
Vandana Tayal and Bhupinder Singh Kalra
Hypertension is one of the major causes of cardiovascular
morbidity. Most patients who are on treatment for hypertension
fail to achieve adequate control with the existing therapy
and rates of cardiovascular morbidity remain high. As the
renin-angiotensin-aldosterone system is strongly implicated
in the development of hypertension-related target organ damage,
intensive efforts have been devoted towards the development
of drugs targeting this system. In addition to angiotensin
converting enzyme (ACE) inhibitors and angiotensin receptor
blockers (ARBs), inhibition of renin has also become a clinical
reality. Aliskiren, a novel renin inhibitor, has overcome
a number of shortcomings of existing drugs and is now available
to address angiotensin production directly at its rate-limiting
step.
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