| Current
Drug Therapy
ISSN: 1574-8855
Current Drug Therapy
Volume 2, Number 2, May 2007
Contents
Editorial Pp. 95
Autism Spectrum Disorders: Etiology and Pharmacotherapy
Pp. 97-103
Mohammad-Reza Mohammadi and Shahin Akhondzadeh
[Abstract]
A Review of the Current Role of Proton Therapy in
Modern Oncology Pp. 105-109
Maurizio Amichetti, Augusto Lombardi, Carlo Algranati,
Marco Schwarz, Marco Cianchetti and Lamberto Widesott
[Abstract]
HIV Management: New Approaches Pp. 111-119
Supriya S. Shidhaye, Pagar Hemant, Haddadi Majid and Vilasrao
Kadam
[Abstract]
Beta-Blocking Agents and Electroconvulsive Therapy
Pp. 121-126
Walter W. van den Broek, Theo H.N. Groenland, Paul G.H.
Mulder, Ari Kusuma, Tom K. Birkenhäger, Esther Pluijms
and Jan A. Bruijn
[Abstract]
Ibopamine Stimulates α-Adrenergic
Receptors and D1 Dopaminergic Receptors in the Eye
Pp. 127-132
Italo Giuffre'
[Abstract]
Transdermal Penetration Enhancers Pp. 133-142
Shaji Jessy, Marathe Shripad and Shah Mansi
[Abstract]
Will Medicinal Cannabinoids Prove to be Useful Clinically?
Pp. 143-150
Paul F. Smith
[Abstract]
Emerging Therapies for Type 2 Diabetes Pp.
151-160
Anthony H. Stonehouse and David G. Maggs
[Abstract]
Treatment of Chronic Pain with Drugs that Modulate
Central Nervous System Serotonin and Norepinephrine
Pp. 161-167
Joachim F. Wernicke, Smriti Iyengar and M. Dolores Ferrer-Garcia
[Abstract]
Abstracts
[Back to top]
Editorial:
The articles in this issue of Current Drug Therapy
illustrate the spectrum of success in our attempts at pharmacotherapy.
At one extreme we have a paper dealing with autism spectrum
disorder, for which no therapies are available to deal with
the underlying disorder (although some of the manifestations
are amenable to treatment), to reviews of diseases for which
a wide variety of treatments are available. These include
reviews of treatments for AIDS and type 2 diabetes.
An appealing explanation for this disparity in therapeutic
options among disease states is that some disease processes
are much more complicated than others, or that the organs
which they affect are of different complexity. Certainly,
the brain (autism) is more complex than immune cells and viruses
(AIDS) and the pancreas (diabetes). Complexity of the disorder
or body system affected probably does not totally explain
why many more therapies are available in some situations than
in others. What also appears to contribute to this disparity
is the fact that the scope of pharmacological intervention
is much more targeted in some situations that in others. For
instance, in the case of AIDS, the goal is to affect the interaction
between a virus and a cell, with targeted inhibition of viral
replication. Similarly, diabetes can be thought of as an interaction
between pancreatic cells, insulin and target cells. Here too,
molecular mechanisms involved have been elucidated, and therapies
are designed to correct these abnormalities. Autism, on the
other hand, appears to involve complex interactions between
multiple systems in the brain, many of which are still poorly
understood. If we could understand abnormal interactions between
individual groups of brain cells, preferably at the level
of receptors, developing a successful therapy would be much
more likely.
The above is certainly an oversimplification of some of the
disorders discussed. If one accepts the general concept however,
it becomes clear that advances in pharmacotherapy are dependent
largely on our understanding of underlying physiology and
pathology.
Joachin F. Wernicke, PhD, MD
Editor in Chief
Lilly Research Laboratory
Indianapolis, IN 46285
USA
WERNICKE_JOACHIM@LILLY.COM
[Back to top]
Autism Spectrum Disorders: Etiology and Pharmacotherapy
Mohammad-Reza Mohammadi and Shahin Akhondzadeh
Autism is a complex neurodevelopmental disorder that forms
part of a spectrum of related disorders referred to as Autism
Spectrum Disorders (ASD). Like other complex neurodevelopmental
disorders (e.g., schizophrenia), ASD is thought to be the
final common pathway of multiple etiological (largely genetic)
and neuropathological mechanisms. In the absence of a biological
marker, ASD is defined behaviorally, its clinical presentation
characterized by impairments in reciprocal social interaction
and in communication with others, and by a preference for
repetitive, stereotyped behaviors. Our understanding of autism
has changed dramatically over the past decade. We now know
that autism is not one disorder, but several closely related
“disorders”, including Asperger syndrome, atypical
autism, and disintegrative disorder. They may involve a range
of behaviors at different ages and degrees of functioning,
thus the term “autism spectrum disorder”. Along
with these changes in classification, there has been a greater
understanding of the causes of autism. Developmental delay,
epilepsy, minor facial and bodily abnormalities, increased
rate of obstetrical complications, an unequal sex ratio, and
extremes of head size represent subtle, but still not clearly
defined, signs that autism is a neuropsychiatric disorder.
It appears that pharmacological interventions may have a limited
role to play in the overall therapy of the autistic child.
Medications may be most helpful in reducing hyperactivity,
impulsivity, and aggressive and obsessive behaviors. For the
development of everyday life skills, one-on-one behavioral
therapy seems to be mandatory.
[Back to top]
A Review of the Current Role of Proton Therapy in
Modern Oncology
Maurizio Amichetti, Augusto Lombardi, Carlo Algranati,
Marco Schwarz, Marco Cianchetti and Lamberto Widesott
Proton therapy (PT) is a high-precision form of radiotherapy.
The interest in clinical application in oncology of PT is
related to its ballistic selectivity capable to adequately
cover the tumor target with high homogeneity, high conformality
and sparing the surrounding organ at risk (OAR), mainly in
the middle-low dose area, with a potential significant reduction
of toxicity and development of radio-induced second tumors.
PT has gained a renewed interest in very recent years after
its first pioneering beginning in Berkeley in 1954 due to
the advancement in treatment planning, delivery systems (gantry),
radiobiological knowledge and clinical imaging. This fact
has permitted the transit of PT from laboratory research structures
to modern clinically-oriented treatment facilities. The results
of PT in some specific sites such as ocular tumors and base
of the skull tumors are well known approaching local control
rates at five years of 100% and 90%, respectively. Indications
are now evolving towards the treatment of other very common
tumors such as lung, head and neck, liver: all of them show
very attractive response rates. A particular interest is now
growing for pediatric tumors considering the possibility of
reducing not only the dose to OAR but also the integral dose.
Integration with chemotherapy represents another challenge
thanks to the possibility of increasing dose intensity of
chemotherapy or total radiation dose and/or reducing the toxicity
of the combined treatment.
[Back to top]
HIV Management: New Approaches
Supriya S. Shidhaye, Pagar Hemant, Haddadi Majid and Vilasrao
Kadam
Development of resistance towards currently used anti-HIV
drugs is an important determinant in the classical drug failure.
Mutations located in the enzymes reverse transcriptase (RT)
or protease are associated with resistance or reduced susceptibility
to the nucleoside reverse transcriptase inhibitors (NRTIs),
non-nucleoside reverse transcriptase inhibitors (NNRTIs),
and protease inhibitors (PIs). Though all the classical nucleoside
RTIs share a common mechanism of action in inhibiting the
RT of HIV, their pharmacological and toxicological profiles
differ dramatically. On the other hand, nonnucleosides RTIs
share a number of common biochemical and pharmacological properties.
HIV PIs are designed to mimic the transition state of hydrolysis
at the active site; such compounds are called analogue inhibitors.
This paper reviews the molecular mechanism of action of the
reverse transcriptase and protease inhibitors, the resistance
to existing drugs and the new drugs which shows better activity
against resistant strains of HIV such as (i) nucleoside RTIs
viz., Racivir, Alovudine, Reverset, Dioxolone guanosine (DXG),
Dioxolone thymidine (DOT), AVX 754, Elvucitabine; (ii) non
nucleoside RTIs viz., Nevirapine, Delavirdine, CP-94707, Dapivirine
(TMC 120), Etavirine (TMC 125 ), Rilpivirine, 695634, Calanolide,
M IV 170, M VO 26048, Efavirenz., TMC 278; (iii) PIs: 640385,
Darunavir (TMC 114) and Tipranavir.
[Back to top]
Beta-Blocking Agents and Electroconvulsive Therapy
Walter W. van den Broek, Theo H.N. Groenland, Paul G.H.
Mulder, Ari Kusuma, Tom K. Birkenhäger, Esther Pluijms
and Jan A. Bruijn
In this review we want to summarize the results of the placebo-controlled
randomized clinical trials with beta-blocking adrenergic agents
during electroconvulsive therapy (ECT), and review the effect
on seizure duration and cardiovascular variables. We searched
for studies in the electronic databases Medline. Keywords
combined in the search were: “beta-adrenergic blocking
agents” and “electroconvulsive therapy”.
The only limitation specified in the search was that the publications
should include only randomized controlled trials.
Esmolol and other beta-blocking adrenergic agents can have
a significant effect on seizure duration during ECT, it shortens
seizure duration, and this effect is probably dose dependent.
Therefore routine administration is not recommended.
Since the relation between seizure duration and efficacy of
ECT is dependent on electrode placement it seems advisable
to use bilateral electrode placement with patients with cardiovascular
risk factors and an indication for use of esmolol during every
session before seizure induction.
In the absence of cardiovascular risk factors but with prolonging
hypertension or tachycardia during ECT sessions, esmolol also
is again preferred. Labetalol is an alternative although,
especially in high dose, the longer half-life can be considered
as a disadvantage. Experiences with landiolol are limited.
[Back to top]
Ibopamine Stimulates α-Adrenergic
Receptors and D1 Dopaminergic Receptors in the Eye
Italo Giuffre'
Ibopamine stimulates α-adrenergic
receptors and D1-dopaminergic receptors in the eye. Ibopamine
is a dopamine analogue and it is hydrolysed to epinine by
the esterases in the aqueous humor. Adrenergic stimulation
determines the non-cycloplegic mydriatic effect, while the
D1-dopaminergic activity is responsible for an increase in
aqueous humor production. Ibopamine is effective as a mydriatic
before and after surgical procedures. Its main uses are: provocative
test in glaucoma; treatment of ocular hypotony; evaluation
of the outflow pathways of the aqueous humor. Ibopamine test
is positive in 92% of patients affected by primary open-angle
glaucoma (POAG), while it is negative in healthy eyes. It
is useful in relatives of glaucomatous patients.
[Back to top]
Transdermal Penetration Enhancers
Shaji Jessy, Marathe Shripad and Shah Mansi
Transdermal drug therapy has been one of the major research
fields in the area of drug therapy for last few decades. However
inspite of its large therapeutic potential market success
has been limited. The most important reason being the barrier
properties of Stratum Corneum. Various approaches had been
tried to breach this barrier .This article briefly reviews
the various approaches used to enhance transdermal penetration.
Penetration enhancers represent a popular method of increasing
drug flux through the skin for local or systemic activity.
The article briefly introduces the properties of skin and
its barrier characteristics. A classification of various penetration
enhancement strategies is given. The following article explores
the promise shown by electrical as well as sonicated transdermal
drug transport as a novel drug delivery system. The paper
details the application of various physical and chemical drugs
in transdermal drug delivery. The paper also briefs on use
of micro fabricated microneedles and biodegradable enhancers
as a novel approach to transdermal drug delivery.
The paper concludes with a brief discussion of the future
prospects of transdermal penetration enhancers, which can
significantly improve the present drug delivery scenario.
[Back to top]
Will Medicinal Cannabinoids Prove to be Useful Clinically?
Paul F. Smith
In some parts of the world, medicinal cannabinoids have already
been used to treat nausea and vomiting associated with chemotherapy
and wasting in diseases such as AIDS and terminal cancer.
However, over the last several years, currently used cannabinoids,
such as dronabinol, as well as newly developed cannabis-based
medicines such as Sativex® (narrow ratio combination of
Δ9-tetrahydrocannabinol
and cannabidiol), have been investigated for the treatment
of spasticity, chronic pain, disruption of sleep and urinary
dysfunction associated with multiple sclerosis and other neurological
disorders. Although some clinical trials have yielded positive
results, others have not and there has been controversy regarding
the use of subjective rating scales to measure pain and spasticity.
Adverse side effects have been generally mild and transient;
however, researchers and clinicians are still concerned about
the prospect of long-term adverse side effects. This review
will summarise and critically evaluate the currently available
clinical trial data.
[Back to top]
Emerging Therapies for Type 2 Diabetes
Anthony H. Stonehouse and David G. Maggs
Type 2 diabetes results from progressive β
cell dysfunction and insulin resistance, leading to progressive
worsening of glycemic control, and increased risk of microvascular
and macrovascular complications.
Traditionally, treatment strategies for type 2 diabetes have
concentrated on compensating for insulin deficiency and reduc-ing
insulin resistance. These approaches sequentially utilize
diet and exercise, oral antidiabetic drug therapy, and ultimately,
exogenous insulin. However, current therapies have little
effect on the inexorable decline of β
cell dysfunction, and in a group of patients already overweight
or obese, treatment often comes with further weight gain.
Consequently, patients often experience deterioration of glycemic
control as their disease progresses while battling obesity.
Several new therapies including new insulin platforms and
new classes of pharmaceutical agents with unique modes of
action have recently been introduced or are in clinical development
for use in patients with type 2 diabetes. These include amylinomimetics,
incretin mimetics, DPP IV inhibitors, and glucagon antagonists.
These new agents improve glycemia and in some instances can
reduce body weight. Furthermore, anti obesity agents, either
currently available or in development, are being investigated
for their potential to treat diabetes. This review focuses
primarily on these new therapeutic approaches, particularly
those that improve glycemic control while improving control
of body weight.
[Back to top]
Treatment of Chronic Pain with Drugs that Modulate
Central Nervous System Serotonin and Norepinephrine
Joachim F. Wernicke, Smriti Iyengar and M. Dolores Ferrer-Garcia
The perception of pain is the result of complicated physiological
and psychological processes. Pain can be treated by interrupting
peripheral inputs, or by modulation of pain signals in the
central nervous system. One approach that has been particularly
successful has involved use of drugs that increase activity
in brain and spinal cord pathways that inhibit transmission
of pain signals. Drugs that increase serotonin and norepinephrine
(Serotonin Norepinephrine Reuptake Inhibitors - SNRIs) have
been found to be effective. These drugs are known to have
antidepressant activity, and are widely used to treat depression.
Although there is overlap between pain and depression, the
reason these drugs are effective for treatment of pain appears
to result from a direct effect on pain pathways in the central
nervous system. Mechanisms of action and clinical utility
of SNRIs in treatment of chronic pain are reviewed.
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