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Current
Drug Safety
ISSN: 1574-8863
Current Drug Safety
Volume 4, Number 1, January 2009
Contents
Editorial:
Lessons from Contaminated Heparin Pp. 1
Seetal Dodd and Frank M.C. Besag
Opinion:
[Full
text article]
Withdrawal of Rimonabant – Walking the Tightrope of
21st Century Pharmaceutical
Regulation? Pp. 2-4
David Taylor
Original Articles
A Multiple-Dose, Open-Label, Safety, Compliance, and Usage
Evaluation Study of Epicutaneously Applied Diractin®
(Ketoprofen in Transfersome®)
in Joint/Musculoskeletal Pain or Soft Tissue Inflammation
Pp. 5-10
Werner Kneer, Ilka Rother, Matthias Rother
and Egbert Seidel
[Abstract] [Full
text article]
[PMID: 19149519 PubMed - indexed for MEDLINE]
Prolonged Exposure to Ketamine Increases Brain Derived
Neurotrophic Factor Levels in Developing Rat Brains Pp.
11-16
Juan C. Ibla, Hideaki Hayashi, Dusica Bajic
and Sulpicio G. Soriano
[Abstract] [Full
text article] [PMID:
19149520 PubMed - indexed for MEDLINE]
Reyes’s Syndrome, Encephalopathy, Hyperammonemia and
Acetyl Salicylic Acid Ingestion in a City Hospital of Buenos
Aires, Argentina Pp. 17-21
Abraham Lemberg, María A. Fernández,
Carlos Coll, Diego O. Rosello, Salvador Romay, Juan C. Perazzo,
Ester J. Filinger
[Abstract] [Full
text article] [PMID:
19149521 PubMed - indexed for MEDLINE]
Safety and Efficacy of Duloxetine in the Treatment of Diabetic
Peripheral Neuropathic Pain in Older Patients Pp.
22-29
Ajay D. Wasan, Melissa J. Ossanna, Joel
Raskin, Joachim F. Wernicke, Michael J. Robinson, Jerry A.
Hall, Sara E. Edwards, Sarah Lipsius, Adam L. Meyers and
Bill H. McCarberg
[Abstract] [Full
text article] [PMID:
19149522 PubMed - indexed for MEDLINE]
Case Report
An Atypical Case of Fulminant Interstitial Pneumonitis Induced
by Carbamazepine Pp. 30-33
Hideyuki Narita, Takuro Ozawa, Takahisa Nishiyama,
Shohei Matsumoto, Seigo Watanabe and Atsushi Isshiki
[Abstract] [Full
text article] [PMID:
19149523 PubMed - indexed for MEDLINE]
Review Articles
Investigating Drug-Induced Mitochondrial Toxicity: A Biosensor
to Increase Drug Safety? Pp. 34-54
Cláudia V. Pereira, Ana C. Moreira, Susana
P. Pereira, Nuno G. Machado, Filipa S. Carvalho, Vilma A.
Sardão and Paulo J. Oliveira
[Abstract] [Full
text article] [PMID:
19149524 PubMed - indexed for MEDLINE]
Drug-Induced Hypokalaemia Pp. 55-61
Chaker Ben Salem, Houssem Hmouda and
Kamel Bouraoui
[Abstract] [Full
text article] [PMID:
19149525 PubMed - indexed for MEDLINE]
Current Management of Vomiting After Tonsillectomy in Children
Pp. 62-73
Yoshitaka Fujii
[Abstract] [Full
text article] [PMID:
19149526 PubMed - indexed for MEDLINE]
Compliance Aids and Medicine Stability: New Evidence of Quality
Assurance Pp. 74-78
Beverley Dawn Glass, Alison Haywood, Victoria
Llewelyn and Martina Mangan
[Abstract] [Full
text article] [PMID:
19149527 PubMed - indexed for MEDLINE]
Biodegradable Polymer-Metal Complexes for Gene and Drug Delivery
Pp. 79-83
Hossein Hosseinkhani and Mohsen Hosseinkhani
[Abstract] [Full
text article] [PMID:
19149528 PubMed - indexed for MEDLINE]
Atypical Neuroleptic Malignant Syndrome or Serotonin Toxicity
Associated with Atypical Antipsychotics? Pp. 84-93
Yuji Odagaki
[Abstract] [Full
text article] [PMID:
19149529 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
Editorial: Lessons from Contaminated Heparin
Most researchers and academics in drug safety focus
their work on the toxicity and side-effect profiles of pharmacologically
active agents. As a professional group, we have become experts
at screening drug candidates for potential to cause harm to
biological systems or potential to interact adversely with
other therapeutic agents. We are vigilant in documenting adverse
events through all phases of clinical trials and post-marketing.
We constantly refine our screening techniques, making use
of the latest available technologies. Consequently, in many
fields of medicine the newer drugs have significantly more
benign adverse-effect profiles than their predecessors. The
public expects safer drugs and new research is delivering
them.
Nevertheless, maintaining drug safety continues to be a difficult
challenge. Discussions about drug safety with our colleagues
in the regulatory authorities suggest that most of their time
is spent not dealing with issues of drug toxicity but is instead
spent dealing with issues of negligence and error. These are
issues that we, as researchers and clinicians, rarely consider.
From reports to US health authorities in January 2008, one
of the most serious recent challenges for drug safety was
recognised when some patients undergoing dialysis were found
to have acute hypersensitivity reactions, subsequently associated
with the contamination of heparin-containing products with
oversulfated chondroitin sulphate (OSCS), an impurity that
is structurally similar to heparin [1]. Clusters of patients
had been having such reactions from November 2007. The symptoms
included, lowered blood pressure, facial swelling, tachycardia,
urticaria and nausea. By April 2008, 81 deaths associated
with contaminated heparin had been reported. Adverse effects
of OSCS-contaminated heparin have been demonstrated in rodent
and swine models, confirming a reduction in diastolic pressure
with administration and that the effect is dependant both
on dose and route of administration [2]. Contaminated heparin
products have been found in Australia, Canada, China, Denmark,
France, Germany, Italy, Japan, The Netherlands, New Zealand
and the United States.
The source of the contamination was traced to a manufacturing
facility in Changzhou, China, which was inspected by investigators
from the US Food and Drug Administration in February 2008.
Many inadequacies were reported with the facility itself,
as well with suppliers of crude materials to the facility
[3]. It is still unclear whether the contamination was accidental
or due to replacing the correct raw materials with a cheaper
substitute.
The impact of the contaminated heparin problem continued throughout
2008. As late as May, new recall notices were being issued
for products, including heparin-coated thoracic drainage catheters
and some devices used in cardiac surgery.
The example of heparin contamination highlights numerous problems
for drug safety. The increasingly global nature of the pharmaceutical
industry means that errors can be on a larger scale, more
difficult to regulate and harder to track to their source.
Industry purchases from networks of manufacturers, each of
which has a further network of corporations and suppliers.
Each supplier and manufacturer has to comply with its own
local laws and regulations as well those of the country where
its products are used. Then there are language and cultural
differences to overcome. This can be a difficult challenge,
even for people with the best of intentions. Industries do
not exist for altruistic reasons of helping the sick. They
are there to make a profit and that brings strong pressures
to minimise costs. However, most pharmaceutical companies
recognise that it is in their own best interests to comply
with safety standards. If they breach standards, not only
do they risk expensive legal process but they also lose credibility,
which means that they lose business. The manufacturers of
contaminated heparin clearly breached regulations.
While traditional toxicology and safety monitoring will continue
to be core research activities for those interested in drug
safety, we should always be prepared to look beyond our traditional
horizons. A potential for error and negligence exists which
can compromise drug safety throughout the manufacturing, distribution
and storage process. Increasing globalisation has heightened
the challenge of providing safe drugs. Let us hope that contaminated
heparin is no more than a consequence of a world adjusting
to new trading relationships and not a sign of things to come.
REFERENCES
[1] Kishimoto TK, Viswanathan K, Ganguly T, et al.
Contaminated heparin associated with adverse clinical events
and activation of the contact system. N Engl J Med 2008; 358:
2457-67.
[2] Kakkar AK, Bonnefoi M. Contaminated heparin. N Engl J
Med 2008; 359: 1292-3.
[3] Friedman RL. Warning letter from the Centre for Drug Evaluation
and Research (http://www.fda.gov/cder/warn/2008/320-08-01.pdf).
Food Drug Admin 2008 [Accessed 25.10.08].
Seetal Dodd
(Co-Editor-in-Chief)
Department of Clinical and Biomedical Sciences
University of Melbourne
Melbourne
Australia
E-mail:SEETALD@BarwonHealth.org.au
Frank M.C. Besag
(Co-Editor-in-Chief)
Specialist Medical Department
Twinwoods Health Resource Centre
Bedfordshire, MK41 6AT
UK
E-mail:Frank.Besag@blpt.nhs.uk
[Back to top]
[PMID:
19149519 PubMed - indexed for MEDLINE]
A Multiple-Dose, Open-Label, Safety, Compliance, and
Usage Evaluation Study of Epicutaneously Applied Diractin®
(Ketoprofen in Transfersome®)
in Joint/Musculoskeletal Pain or Soft Tissue Inflammation
Werner Kneer, Ilka Rother, Matthias Rother
and Egbert Seidel
[Full
text article]
The risk of oral NSAID including Cox-2 inhibitors to
cause gastrointestinal, renal or cardiovascular adverse events
related to systemic drug exposure could be reduced by local
application. But only few long-term studies have been published
to show safety and efficacy for long-term use of topical NSAID´s.
Diractin®
(formerly IDEA-033) is a viscous, aqueous formulation for
epicutaneous application of ketoprofen based on ultra-deformable,
self-regulating carrier (Transfersome®).
This multiple-dose, open label study with treatment periods
up to 18 months included 402 patients with joint pain, musculoskeletal
pain, stiffness or soft tissue inflammation (age of 61.4 ±
11.5 years). Most of the patients suffered from os-teoarthritis
(OA) of the knee (68.9%). Diractin®
was applied epicutaneously up to twice daily with a maximum
dose of 220 mg ketoprofen per a maximum of 2 application sites.
The mean pain score at baseline was 5.4 ±1.4
on a 10 point categorical scale. During the study the pain
score progressively improved up to week 36 (3.5±1.9)
without a substantial further change during the rest of observation
period of up to 18 months. The reduction of pain scores between
week 0 (baseline) and at all later visits was statistically
significant (P <
0.0001). Patients also reported an improvement of quality
of life on the EUROQoL. The majority of treatment related
adverse events were skin and subcutaneous tissue disorders
with the highest frequency reported for erythema (16.7%) and
pruritus (2.0%). Systemic ketoprofen exposure remained low
throughout the study period with plasma concentrations of
less than 1% of what was reported for a single, standard oral
dose of 200 mg ketoprofen. There were no occurrences of treatment
related serious adverse events and no remarkable changes in
laboratory values or vital signs.
In summary, Diractin®
provided adequate pain relief with a good safety and tolerability
profile when used for up to 18 months (72 weeks).
[Back to top] [PMID:
19149520 PubMed - indexed for MEDLINE]
Prolonged Exposure to Ketamine Increases Brain Derived
Neurotrophic Factor Levels in Developing Rat Brains
Juan C. Ibla, Hideaki Hayashi, Dusica Bajic
and Sulpicio G. Soriano
[Full
text article]
Prolonged exposure to ketamine, a NMDA receptor antagonist,
results in accelerated neurodegeneration and attenuated weight
gain in neonatal rats. Suppression of the NMDA receptors by
non-competitive antagonists has resulted in conflicting reports
of both increased and decreased expression of BDNF. To examine
the effect of prolonged ketamine exposure on BDNF expression,
we administered saline or ketamine (20mg/kg) at 90-minute
intervals over 9 hours to postnatal day 7 (P7) rat pups. The
ketamine-treated rat pups had increased neurodegeneration,
BDNF and TrkB cDNA products and protein levels. This increased
expression of BDNF may be a response to ketamine-induced injury.
[Back to top] [PMID:
19149521 PubMed - indexed for MEDLINE]
Reyes’s Syndrome, Encephalopathy, Hyperammonemia
and Acetyl Salicylic Acid Ingestion in a City Hospital of
Buenos Aires, Argentina
Abraham Lemberg, María A. Fernández,
Carlos Coll, Diego O. Rosello, Salvador Romay, Juan C. Perazzo,
Ester J. Filinger
[Full
text article]
Twelve cases of Reye’s syndrome are presented with
different degrees of encephalopathy, hyperammonemia and hypoglycemia;
associated to acetyl salicylic acid (ASA) ingestion. The aim
of the present retrospective study was to describe our experience
in selected patients with Reye’s syndrome associated
to the ASA ingestion and to underline the influence of hyperammonemia
on Reye’s encephalopathy. All the cases presented moderate
hyperbilirubinemia, elevated alanine aminotransferase, aspartate
aminotransferase with an average of 302±205
UI/L and 285±149
UI/L respectively. Arterial blood ammonia averaged 172.4±71.3
µmol/L and glycaemia averaged 35.2±17.0
mg/dl. A high mortality was found in our series (41.7%). Considering
that encephalopathy is the leading syndrome in these cases,
the influence of ammonia on brain tissue was described. Glutamate
is an excitotoxic neurotransmitter, capable to produce neuron
and astrocyte damage and apoptosis. The presence of ASA could
cause the onset of the mitochondrial permeability transition
and the mitochondrial swelling in the astrocyte, leading to
hyperammonemia. In Reye’s syndrome, hyperammonemia and
perhaps the increase of glutamate are the leading factors
in the mechanism of brain damage and encephalopathy. Aspirin
must be carefully administrated and controlled by professionals.
Furthermore, parents must be informed about the risks in the
use of this drug in children.
[Back to top] [PMID:
19149522 PubMed - indexed for MEDLINE]
Safety and Efficacy of Duloxetine in the Treatment
of Diabetic Peripheral Neuropathic Pain in Older Patients
Ajay D. Wasan, Melissa J. Ossanna, Joel
Raskin, Joachim F. Wernicke, Michael J. Robinson, Jerry A.
Hall, Sara E. Edwards, Sarah Lipsius, Adam L. Meyers and
Bill H. McCarberg
[Full
text article]
Objective: We present a post-hoc analysis of the safety
and efficacy of duloxetine, a selective serotonin/norepinephrine
reuptake inhibitor, for treatment of diabetic peripheral neuropathic
pain (DPNP) in older patients.
Methods: Data from three double-blind, placebo-controlled
trials in adult patients with DPNP were pooled and stratified
by age (<65,
≥65
years). Patients were randomized to duloxetine (DLX) 60 mg
once-daily, 60 mg twice-daily, or placebo for 12 weeks, followed
by a 52-week extension phase (re-randomization to routine
care or DLX 120 mg/day). Intent-to-treat analyses were used
for safety and efficacy assessment.
Results: In the acute phase, overall TEAE rates did
not differ significantly by age. A greater percentage of older
patients discontinued due to TEAEs (P<0.001),
regardless of treatment group. Duloxetine improved weekly
mean 24-hour average pain scores versus placebo in both age
groups (P<0.01).
In the extension phase, a significant therapy-by-age interaction
(P<0.05)
was observed in overall TEAE rate; with routine care, 86.6%
of older patients had ≥1
TEAE versus 74.6% of younger patients.
Conclusions: Although TEAEs more frequently lead
to discontinuation in older patients, duloxetine was well
tolerated and efficacious for treatment of DPNP regardless
of age. These data suggest duloxetine may be beneficial for
treatment of DPNP in patients ≥65.
[Back to top] [PMID:
19149523 PubMed - indexed for MEDLINE]
An Atypical Case of Fulminant Interstitial Pneumonitis
Induced by Carbamazepine
Hideyuki Narita, Takuro Ozawa, Takahisa Nishiyama,
Shohei Matsumoto, Seigo Watanabe and Atsushi Isshiki
[Full
text article]
Carbamazepine is a therapeutic anticonvulsant, used to
manage pain. We often use it to treat trigeminal and post-herpes
zoster neuralgias. Interstitial pneumonitis (IP) is a known
adverse consequence of using carbamazepine, with bronchiolitis
obliterans and organizing pneumonitis. (BOOP) drug-induced
IP as typical examples. Here we described a patient with post-herpes
zoster neuralgia, who suffered from drug-induced acute IP
that differed from cases typically induced by carbamazepine.
[Back to top] [PMID:
19149524 PubMed - indexed for MEDLINE]
Investigating Drug-Induced Mitochondrial Toxicity:
A Biosensor to Increase Drug Safety?
Cláudia V. Pereira, Ana C. Moreira, Susana
P. Pereira, Nuno G. Machado, Filipa S. Carvalho, Vilma A.
Sardão and Paulo J. Oliveira
[Full
text article]
Mitochondria are recognized as the producers of the majority
of energy cells need for their normal activity. After the
initial comprehension of how mitochondrial oxidative phosphorylation
produces energy, mitochondrial research was not a priority
for most cell biologists until novel mitochondrial functions
were identified. In fact, it is now known that mitochondria
are not only involved in cell calcium homeostasis, intermediate
metabolism and free radical generation but are also a crucial
crossroad for several cell death pathways. The notion that
several clinically used drugs and other xenobiotics induce
organ degeneration through damaging mitochondrial bioenergetics
led to the use of the organelle as an effective and reliable
bio-sensor to predict drug safety. Classic methods used to
test the toxicity of a wide range of compounds on isolated
mitochondrial fractions were later replaced by novel high-throughput
methods to investigate the safety of a very large number of
new molecules. Without surprise, the assessment of “mitochondrial
safety” for new discovered molecules is of clear interest
for pharmaceutical companies which can now select compounds
lacking mitochondrial toxicity to undergo further trials,
thus avoiding the possibility of later human toxicity due
to mitochondrial liabilities.
[Back to top] [PMID:
19149525 PubMed - indexed for MEDLINE]
Drug-Induced Hypokalaemia
Chaker Ben Salem, Houssem Hmouda and
Kamel Bouraoui
[Full
text article]
Hypokalaemia (defined as a plasma potassium concentration
<3.5
mEq/L) is a common electrolyte abnormality in clinical practice.
Drugs are a common cause of either asymptomatic or symptomatic
hypokalaemia. Drug-induced hypokalaemia is an important problem
particularly in the elderly and in patients with cardiovascular,
renal or hepatic disease. Hypokalaemia can complicate the
use of the drug in the therapeutic concentration range, and
can also be precipitated with overdose or conditions leading
to drug intoxication. Because the etiologies of hypokalaemia
are numerous, the diagnosis of drug-induced hypokalaemia may
be overlooked. Physicians should always pay close attention
to this common side effect. Evaluation and management of a
hypokalaemic patient should include a careful review of medications
history to determine if a drug capable of causing or aggravating
this electrolyte abnormality is present.
[Back to top] [PMID:
19149526 PubMed - indexed for MEDLINE]
Current Management of Vomiting After Tonsillectomy
in Children
Yoshitaka Fujii
[Full
text article]
Postoperative vomiting (POV) continues to be a common
complication in children undergoing tonsillectomy with or
without adenoidectomy. The incidence of POV is between 62%
and 73% when no prophylactic antiemetic is given.
Numerous antiemetics have been studied for the management
of POV after pediatric tonsillectomy. As traditional antiemetics,
benzamides (e.g., metoclopramide), butyrophenones (e.g., droperidol),
phenothiazines (e.g., perphenazine), and antihistamines (e.g.,
dimenhydrinate) are used for POV. The available nontraditional
antiemetics are propofol, dexamethasone, and midazolam. Serotonin
receptor antagonists, which include ondansetron, granisetron,
tropisetron, dolasetron, and ramosetron, are more effective
than traditional antiemetics. However, these drugs are not
entirely effective, perhaps because most of them act through
the blockade on one type of receptor. Combination antiemetic
therapy with a serotonin receptor antagonist (ondansetron,
granisetron, tropisetron) plus droperidol or dexamethasone
is highly effective for the prophylaxis against POV. Nonpharmacological
techniques include acustimulation, acupressure, and acupuncture
at P6 (Nei-Kuwan) point.
Most of published trials indicate an improved antiemetic prophylaxis
in children undergoing tonsillectomy with or without adenoidectomy
when risk factors for POV would be avoided and/or effective
antiemetic therapy would be performed. For the prevention
of POV after pediatric tonsillectomy, baseline risk factors,
including patient characteristics, surgical procedure, anesthetic
techniques, and postoperative care, should be avoided, if
possible. Clinicians should also consider these clinical strategies
as mentioned above for the prevention of POV after tonsillectomy
in children.
[Back to top] [PMID:
19149527 PubMed - indexed for MEDLINE]
Compliance Aids and Medicine Stability: New Evidence
of Quality Assurance
Beverley Dawn Glass, Alison Haywood, Victoria
Llewelyn and Martina Mangan
[Full
text article]
Although increasing use of compliance aids is resulting
in improved clinical outcomes for patients, the stability
of some drugs being repackaged into these aids is being questioned.
This is due to the fact that despite their widespread use,
there is limited availability of relevant stability data.
This review presents clinical evidence for repackaging into
Dose Administration Aids (DAAs), the Australian Pharmaceutical
Advisory Committee and other guidelines on general stability
issues related to repackaging and a summary of evidence for
stability studies conducted in the practice.
For frusemide and prochlorperazine chosen as candidates for
study because of their light sensitivity, while discoloration
on light exposure rendered them unacceptable for patient use,
precautions in repackaging and patient counselling can easily
overcome this problem. In the case of sodium valproate however,
hygroscopicity results in these tablets being unusable after
exposure to accelerated storage conditions.
In the absence of specific data on the stability of drug products
repackaged into compliance aids, the guidelines, practical
recommendations for repackaging and the management of compliance
aids put forward in this article provide the pharmacist with
the tools to make an informed decision on this process.
[Back to top] [PMID:
19149528 PubMed - indexed for MEDLINE]
Biodegradable Polymer-Metal Complexes for Gene and
Drug Delivery
Hossein Hosseinkhani and Mohsen Hosseinkhani
[Full
text article]
The delivery of genes and drugs into cells has increasingly
attracted attention for the generation of genetically engineered
cells. Successful drug delivery will have enormous academic,
clinical, and practical impacts on gene therapy, cell and
molecular biology, pharmaceutical and food industries, and
bio-production. The major aim of gene therapy is to deliver
genetic materials into cells effectively, genetically modifying
and repairing cell functions with the possibility of inducing
therapeutic healing of disease. The genetic material includes
DNA, RNA, antisense, decoy DNA, and ribozymes. The aim is
that the appropriate transfection would allow diseased cells
to return to a healthy condition. The genetic manipulation
is often manifested in the mechanisms of intracellular actions
of genes and proteins, and may play an important role in making
clear the key genes associated with various diseases. Based
on fundamental and scientific knowledge, the delivery technology
of genetic material should be applicable to producing various
proteins of pharmaceutical value (e.g. cytokines, growth factors,
and antibodies) and also to producing seeds resistant to harmful
insects and cold weather damage. This implies that the cells
might be enhanced to produce valuable pharmaceutical and food
products.
For each approach, it is important, for successful gene expression,
to select an appropriate gene to be delivered as well as to
develop the gene delivery technology to enhance transfection
efficiency. This review will provide an overview of the enhanced
gene expression of plasmid DNA complexed wier-metal complex,
introducing our recent research data to emphasizeth new non-viral
gene delivery vehicles by biodegradable biopolym the technical
feasibility of biopolymer-metal complexes in gene therapy
and biotechnology.
[Back to top] [PMID:
19149529 PubMed - indexed for MEDLINE]
Atypical Neuroleptic Malignant Syndrome or Serotonin
Toxicity Associated with Atypical Antipsychotics?
Yuji Odagaki
[Full
text article]
Atypical antipsychotics and selective serotonin reuptake
inhibitors (SSRIs) have been prescribed extensively, often
in combination with each other. When toxic encephalopathy
develops with neuromuscular and autonomic symptoms in a patient
taking medication including atypical antipsychotics, it has
tended to be diagnosed as neuroleptic malignant syndrome (NMS).
However, there have recently been several case reports where
the diagnosis of serotonin syndrome is given or raised as
a likely differential diagnosis to such cases. In the present
review, the author addressed himself to the issues surrounding
the neurotoxic reaction to the treatment regimen containing
atypical antipsychotics, focusing on the “atypical”
forms of NMS and pathophysiological as well as clinical features
of serotonin toxicity. Although NMS is idiosyncratic in nature,
it appears practically useful to comprehend this syndrome
as a spectrum-based concept. Likewise, serotonin toxicity
is a broad spectrum of clinical syndromes in close connection
with serotomimetic drug use, including varied severity. Some
of atypical antipsychotics, i.e., perospirone, aripiprazole,
ziprasidone, clozapine, and quetiapine, have been shown to
behave as partial agonists at 5-HT1A
receptors, providing direct evidence that these atypical antipsychotics
are serotomimetic per se. The reciprocal interaction
between the dopaminergic and serotonergic systems disturbed
by either dopaminergic blockers or serotonergic enhancers
leads to the disruption of homeostasis, with typical forms
of NMS and serotonin syndrome representing the ends of the
common pathophysiological background. The practical and flexible
way to consider and manage such cases with updated knowledge
derived from basic research should be warranted to be beneficial
to our patients.
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