| Current
Drug Therapy
ISSN: 1574-8855
Current Drug Therapy
Volume 1, Number 1, January 2006
Contents
Pharmacotherapy of schizophrenia: The past, present
and future Pp. 1-7
Shahin Akhondzadeh
[Abstract] [Full
Text Article]
Cerebral White Matter Lesions, Risk of Stroke, and
Cerebrovascular Protection with Angiotensin Receptor Blockers
Pp. 9-16
Alejandro de la Sierra & Cristina Sierra
[Abstract] [Full
Text Article]
Pharmacological support of Neurorehabilitation
Pp. 17-22
Burkhard Pleger & Patrick Ragert
[Abstract] [Full
Text Article]
Ovulation induction in anovulatory patients with polycystic
ovary syndrome Pp. 23-29
Stefano Palomba, Angela Falbo, Tiziana Russo & Fulvio
Zullo
[Abstract] [Full
Text Article]
The Effects of Soy Isoflavones in Postmenopausal Women:
Clinical Review Pp. 31-36
Eliana Aguiar Petri Nahas & Jorge Nahas-Neto
[Abstract] [Full
Text Article]
Pharmacotherapy for Premature Ejaculation
Pp. 37-46
M.R. Safarinejad & S.Y Hosseini
[Abstract] [Full
Text Article]
Role of Angiotensin-1-Receptor Blockers In Cardiorenal
Disease Pp. 47-54
René R. Wenzel
[Abstract] [Full
Text Article]
Clinical pharmacology of cyclophosphamide and ifosfamide
Pp. 55-84
Shu-Feng Zhou, Jing Zhang & Quan Tian
[Abstract] [Full
Text Article]
Enantiomeric Local Anesthetics: Can Ropivacaine and
Levobupivacaine Improve Our Practice? Pp. 85-89
Andrea Casati & Marco Baciarello
[Abstract] [Full
Text Article]
Revival of the Lens Transparency with N- Acetylcarnosine
Pp. 91-116
Mark A. Babizhayev, Anatoly I. Deyev, Valentina N. Yermakova,Valerii
V. Remenshchikov & Johan Bours
[Abstract] [Full
Text Article]
Fluoroquinolones in Pediatrics Pp. 117-125
Adriano Arguedas , Hernan Sierra & Carolina Soley
[Abstract] [Full
Text Article]
Intranasal Drug Delivery for Children with Acute Illness
Pp. 127-130
R.D. Goldman
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Pharmacotherapy of schizophrenia: The past, present
and future
Shahin Akhondzadeh
[Full
Text Article]
Traditionally, schizophrenia was considered to be a severe
psychiatric disorder, with a chronic course and an unfavorable
outcome. Throughout history, there has been incidence of schizophrenia,
roughly one percent of the population, consistently, in every
culture. It is generally acknowledged that schizophrenia has
multifactorial etiology, with multiple susceptibility genes
interacting with environmental insults to yield a range of
phenotypes in the schizophrenia spectrum. The discovery of
antipsychotics in the 1950s revolutionized the treatment of
schizophrenia and focused on the positive symptoms. By the
1960s, however, it became obvious that the reduction in positive
symptoms did not lead to recovery from schizophrenia and did
not improve the functional outcome significantly. The advent
of the novel antipsychotics during the last 15 years represents
a significant improvement over the effectiveness of conventional
antipsychotics. However, these agents are not a magic bullet
and are associated with their own attendant treatment complications,
such as weight gain, diabetes, hyperprolactenemia, and QTc
prolongation. Nevertheless, at this point, they seem to be
more effective and safer than conventional antipsychotics.
Moreover, advances in the treatment of schizophrenia have
been and continue to be urgently needed.
[Back to top]
Cerebral White Matter Lesions, Risk of Stroke, and Cerebrovascular
Protection with Angiotensin Receptor Blockers
Alejandro de la Sierra & Cristina Sierra
[Full Text Article]
The pathogenesis and clinical significance of cerebral white
matter lesions (WML) remain controversial. Various studies
have shown that age, hypertension, diabetes mellitus and a
history of stroke or heart disease are the most important
factors related to cerebral WML. Other studies suggest that
WML are closely related to the development of future strokes
and other forms of cerebrovascular disease, such as cognitive
impairment, in elderly patients with vascular risk factors,
particularly hypertension.
Angiotensin receptor blockers are antihypertensive drugs
useful for the treatment of hypertension and cardiovascular
diseases. Recent data from experimental studies and clinical
trials suggest that they could be superior to other antihypertensive
therapies in preventing the development of cerebrovascular
disease and in reducing the risk of death and recurrences
in patients with a previous stroke.
This paper reviews the clinical importance of cerebral WML,
their relationship with stroke development and data concerning
cerebrovascular protection with angiotensin receptor blockers.
[Back to top]
Pharmacological support of Neurorehabilitation
Burkhard Pleger & Patrick Ragert
[Full Text Article]
The administration of numerous excitatory drugs is reported
to facilitate neurorehabilitation. First evidence for this
possible beneficial influence arose from studies investigating
the pharmacology of learning in healthy humans. Amphetamine,
for example, has shown to improve learning of different somatosensory
and motor skills. Paired with physical therapy in stroke patients,
it also increases the rate and extent of motor recovery and
supports treatment of aphasia. Amphetamine is however known
as a "dirty drug" because it acts non-specifically
by increasing centrally the levels of dopamine, serotonin,
and noradrenaline. Thus, first approaches intend to scrutinize
the role of more specifically acting pharmacological agents
on learning and neurorehabilitation.
In this review, focus is placed on two main topics: (i) studies
that aimed to investigate the pharmacology of motor and sensory
skills in healthy humans and (ii) studies investigating whether
the same drugs may also support neurorehabilitation. First,
different motor and sensory paradigms are discussed which
were introduced to investigate basic influences of excitatory
pharmaceuticals on cortical plasticity. Then, emphasis is
placed on the role of these drugs acting to gate synaptic
plasticity in neurorehabilitation. It is concluded that further
studies should focus on more specifically acting pharmaceuticals
supporting different patterns of physical therapy.
[Back to top]
Ovulation induction in anovulatory patients with polycystic
ovary syndrome
Stefano Palomba, Angela Falbo, Tiziana Russo &
Fulvio Zullo
[Full Text Article]
Ovarian dysfunction is probably the pivotal feature of polycystic
ovary syndrome (PCOS) making this syndrome the major cause
of anovulatory infertility in developed countries. Several
approaches have been proposed to induce ovulation in PCOS
patients. Notwithstanding lifestyle modifications, clomiphene
citrate, surgery and, finally, gonadotropins are the classical
and still effective therapeutic options, new drugs, such as
metformin and aromatase inhibitors, are today available in
the treatment of anovulation related to PCOS. The aim of the
present review is to describe all therapeutic approaches to
the anovulatory PCOS patients.
[Back to top]
The Effects of Soy Isoflavones in Postmenopausal Women:
Clinical Review
Eliana Aguiar Petri Nahas & Jorge Nahas-Neto
[Full Text Article]
The hormonal therapy (HT) is recommended for postmenopausal
women primarily for the relief of vasomotor symptoms, treatment
of atrophic vaginitis, and prevention of osteoporosis. Despite
these important benefits, only 35% to 40% of the women ever
start HT, and many do not continue it. The reasons for discontinuation
include resumption of bleeding, perceived risks of breast
cancer, unacceptable side effects and the belief that treatment
is no longer necessary. As a result, there is an increasing
interest in the use of plant-derived estrogens, also known
as phytoestrogens, which seem to be very promising. Isoflavones
is the most investigated subgroup of phytoestrogens. They
are attenuated estrogens and behave both in vivo
and in vitro as agonists and antagonists. The highest
concentrations of isoflavones are found primarily in soy beans.
In this study, the effects of soy isoflavones on postmenopausal
women were reviewed.
[Back to top]
Pharmacotherapy for Premature Ejaculation
M.R. Safarinejad & S.Y Hosseini
[Full Text Article]
Aim.To provide an overview of current
knowledge on pharmacotherapy of premature ejaculation (PE)
Materials and Methods. A comprehensive
review of the literature was conducted using MEDLINE and analysis
of cross-references. The key points of methodology and pharmacology
of various articles have been analysed and critically reviewed.
Results. PE may have significant
negative impact on quality of life. Various recommendations
for drug treatment of PE have been found in the available
literature, varying from anesthetic ointments to various antidepressants
and phosphodiesterase inhibitors. Due to disturbing side effects,
various drugs are not suitable for general use. On the other
hand, topical anesthetics, clomipramine and some SSRIs have
repeatedly been found safe and effective to delay ejaculation.
Conclusions. Remarkable progress
has been made in the treatment of PE. Further research into
the neural, psychological and molecular mechanisms involved
in PE will lead to the development of even safer, more effective
and more convenient therapies for men with PE.
[Back to top]
Role of Angiotensin-1-Receptor Blockers In Cardiorenal
Disease
René R. Wenzel
[Full Text Article]
Arterial hypertension is one of the most important risk factors
for cardiovascular disease. Angiotensin-1-receptor blockers
(ARB) are a class of drugs that potently inhibit the vasoconstriction
and other vascular effects of angiotensin including proliferation
of vascular smooth muscle cells by selective binding to the
AT1-receptor. The present review summarizes the most relevant
experimental and clinical data on this new class of drugs.
ARBs inhibit effects of angiotensin II on the vasoconstriction
and proliferation of vascular smooth muscle cells, reduce
sympathetic activation, increase bradykinin dependent vasodilator
effects and increase Ang(1-7), a metabolite of angiotensin,
which has vascular protective properties. ARBs also interfere
with the interactions of the renin-angiotensin-system with
both the endothelin-system and the sympathetic nervous system.
Under in vivo conditions in men, ARBs have a potent
antihypertensive effect and have fewer side effects than any
other class of antihypertensives. The available ARBs differ
regarding their metabolism, plasma half-life and trough-to-peak-ratio.
Several clinical trials have proven, that ARBs are safe and
effective in reducing morbidity and mortality in hypertension,
diabetic and non-diabetic renal disease, acute myocardial
infarction as well as systolic and diastolic heart failure.
Importantly, protection from cerebrovascular disease and from
cardiovascular disease after stroke is an emerging property
of ARBs and is likely to be partially independent from the
blood-pressure lowering effects. ARBs – similarly to
ACE-inhibitors and in contrast to diuretics – have proven
to reduce the incidence on new-onset diabetes, which is likely
to be clinically relevant in the chronic treatment of hypertension
and cardiac disease. Furthermore, ARBs reduce the incidence
of atrial fibrillation in hypertensive patients. The reasons
for these beneficial effects of ARBs are discussed and include
improvement of endothelial function and renal haemodynamics,
reduction in central nervous sympathetic tone, interaction
with the endothelin-system and potent reduction of left ventricular
hypertrophy.
Thus, ARBs are an important new, well-tolerated class of
cardiovascular drugs, which reduce morbidity and mortality
from cardiac, renal and cerebrovascular disease.
[Back to top]
Clinical pharmacology of cyclophosphamide and ifosfamide
Shu-Feng Zhou, Jing Zhang & Quan Tian
[Full Text Article]
The oxazaphosphorine cyclophosphamide (CPA) and ifosfamide
(IFO) are two commonly used DNA-alkylating agents in cancer
chemotherapy. This review highlights the pharmacokinetics
and pharmacodynamics of the two important agents. As alkylating
agents, CPA and IFO are usually combined with other anticancer
drugs in the chemotherapy of solid tumors and hematological
malignancies to obtain synergistic or additive anticancer
effect due to complementary mechanism of action. Both compounds
are prodrugs that are activated via 4-hydroxylation
by cytochrome P450s such as CYP2B6 and CYP3A4 to generate
alkylating nitrogen mustards (phosphoramide mustard and ifosfamide
mustard) and the byproduct acrolein. The resultant mustards
can alkylate DNA to form DNA-DNA cross-links, leading to inhibition
of DNA synthesis and cell apoptosis. Both CPA and IFO are
also inactivated by N-dechloroethylation, resulting
in N-dechloroethylated metabolites and the byproduct chloroacetaldehyde.
Acrolein is the causative agent for hemorrhagic cystitis,
whereas chloroacetaldehyde induces nephrotoxicity and neurotoxicity.
Pharmacokinetics of CPA and IFO is markedly influenced by
route of administration and duration of treatment, age, co-medication,
liver and renal function. Large interpatient variability in
pharmacokinetics, clinical response rate and toxicity has
been observed in cancer patients treated with CPA or IFO.
Resistance to CPA or IFO occurs, due to decreased activation
by CYP3A4 and CYP2B6, increased deactivation of the agents,
decreased entry into or increased efflux from tumor cells,
increased cellular thiol level, increased DNA repair capacity,
and/or deficient apoptotic response to DNA damage. A full
understanding of factors affecting the pharmacokinetics, pharmacodynamics,
toxicology and pharmacogenetics of CPA and IFO is important
to optimize the dose and regimens of CPA and IFO in cancer
chemotherapy.
[Back to top]
Enantiomeric Local Anesthetics: Can Ropivacaine and Levobupivacaine
Improve Our Practice?
Andrea Casati & Marco Baciarello
[Full Text Article]
The novel, long-acting local anesthetics (LAs) ropivacaine
and levobupivacaine were developed to offer a safer alternative
to bupivacaine. The well-known toxic effects of bupivacaine
on the central nervous system and the cardiovascular system
seem to be less severe when comparable plasma levels of these
pure levorotatory agents are reached. Although there is evidence
of greater safety in the experimental setting, its actual
impact on clinical practice remains unclear. Randomized, controlled
trials using clinical endpoints have shown that the enantiomeric
LAs are viable alternatives to bupivacaine, and may offer
advantages in some settings where a greater differentiation
between motor and sensory block may become evident. The available
evidence seems to support the use of the novel LAs over bupivacaine
whenever large doses are used or the risk of unintended intravascular
injection is high, such as in continuous epidural analgesia
or peripheral nerve blocks.
[Back to top]
Revival of the Lens Transparency with N- Acetylcarnosine
Mark A. Babizhayev, Anatoly I. Deyev, Valentina N.
Yermakova, Valerii V. Remenshchikov & Johan Bours
[Full Text Article]
The risk, cost and social requirement factors drive the investigation
of pharmaceutical approaches to the management of cataracts.
The role of free-radical-induced lipid oxidation (LPO) in
the development of cataracts has been identified. Initial
stages of cataract are characterized by the accumulation of
primary (diene conjugates, cetodienes) LPO products,while
in later stages there is a prevalence of LPO fluorescent end
products. Reliable increase in oxiproducts of fatty acyl content
of lenticular lipids was shown by a direct gas chromatography
technique producing fatty acid fluorine-substituted derivatives.
The lens opacity degree correlates with the level of the LPO
fluorescent end product accumulation in its tissue, accompanied
by SH group oxidation of lens proteins due to a decrease of
reduced glutathione concentration in the lens. The injection
of LPO products into the vitreous was shown to induce cataract.
Peroxide damage of the lens fiber membranes may be the initial
cause of cataract formation. The authors developed N-Acetylcarnosine
ophthalmic drug with lubricant carboxymethylcellulose in eye
drops (NAC, Can-CTM, Nu-EyesTM) suitable
for the non-surgical prevention and treatment of age-related
cataracts. The NAC ophthalmic drug protects the crystalline
lens from oxidative stress-induced damages and in a recent
clinical trial it was shown to produce an effective, safe
and long-term improvement in sight. When administered topically
to the eye, NAC drug functions as a time–release prodrug
form of L-carnosine resistant to hydrolysis with carnosinase
and significantly increases the intraocular uptake of L-carnosine
in the aqueous humor. The mechanisms of prevention and reversal
of cataracts with NAC ophthalmic drug are considered which
include prevention by the intraocular released carnosine of
free-radical-induced inactivation of proprietary lens antioxidant
enzymes (superoxide dismutase), prevention of carbohydrate
and metal-catalysed autooxidation of ascorbic acid –induced
cross-linking glycation reactions to the lens proteins, universal
antioxidant and scavenging activity towards lipid hydroperoxides,
aldehydes and oxygen radicals, activation with L-carnosine
ingredient of proteasome activity in the lens. In this study
the clinical effects of a topical solution of NAC ophthalmic
drug on lens opacities were examined in patients with cataracts
and canines with age-related cataracts. The positive effect
on lens clarity and clarifying modification of opacification
zones is demonstrated. The data suggest a potential and show
the efficacy of developed NAC ophthalmic drug for a positive
effect of treatment (both reversal and prevention) of age-related
cataracts. Innovative Vision Products, Inc. is a holder of
the worldwide patent (including PCT International Publication
Number WO 2004/028536 A1) for the application of N-acetylcarnosine
for the treatment of ophthalmic disorders including cataracts.
[Back to top]
Fluoroquinolones in Pediatrics
Adriano Arguedas, Hernan Sierra & Carolina Soley
[Full Text Article]
The fluoroquinolones (FQ) are a group of antimicrobials with
a broad spectrum of activity against gram positive and gram
negative organisms, intracellular and anaerobic organisms.
These antimicrobial agents have excellent oral bioavailability,
high tissue penetration, low protein binding and a long elimination
half life. The experience with these antibiotics in children
has been limited to certain conditions mainly in the treatment
of bronchopulmonary exacerbations in children with cystic
fibrosis and in the ambulatory treatment of children with
fever and neutropenia. Despite the limited use, it is recognize
that there are other potential indications for the use of
FQ in pediatrics such as for the treatment of children with
bacterial meningitis, refractory and recurrent otitis media,
pneumonia, multiply resistant salmonellosis and shigellosis
and complicated urinary tract infections. Furthermore, the
new FQ have shown excellent in-vitro activity against penicillin-resistant
Streptococcus pneumoniae suggesting that these agents
may be an attractive alternative for the treatment of conditions
that involve these problematic strains. Cartilage toxicity
due to FQ had been a major concern however; the previous experience
with ciprofloxacin and recently the results from long term
(12 months) prospective studies have found no evidence of
such a problem in children. Ciprofloxacin was recently approved
for the treatment of children with complicated urinary tract
infections. If based on the safety and clinical results of
ongoing clinical trials, other new FQ are approved for the
treatment of other conditions in children, particularly respiratory
tract diseases, caution is highly recommended to avoid selection
of bacterial resistance.
[Back to top]
Intranasal Drug Delivery for Children with Acute
Illness
Ran D. Goldman
[Full Text Article]
Management of pain and anxiety for children
requiring urgent care has progressed dramatically in the past
decade. However, the administration of analgesia and sedation
in children is inconsistent, with significant practice variation
among practitioners, and especially amid younger children
who receive less than optimal analgesia.
Nasal administrations of drugs have several
significant advantages over current practices. The nose has
a very rich vascular supply, it facilitates direct absorption
to the systemic blood supply and increases bioavailability
of the drug, compared to oral administration.
The current review summarizes available information
on the use of intranasal drug delivery for children in acute
illness. Midazolam (Versed), Fentanyl, Diamorphine and Ketamine
are discussed, as well as pitfalls and caveats of intranasal
drug use.
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