Robert NAVIAUX, et al.
Suramin vs Autism
Suramin and Autism
Scott LaFee, firstname.lastname@example.org
Suramin is a 100-year-old drug developed to treat African sleeping
sickness and river blindness. Though it has been investigated for
other diseases, including cancer, it is not approved for any
therapeutic use in the United States.
However, a small, randomized clinical trial conducted by Robert
Naviaux, MD, PhD , professor of medicine, pediatrics and
pathology, and colleagues at University of California San Diego
School of Medicine have found that a single intravenous dose of
suramin produced dramatic, but transient, improvement of core
symptoms of autism spectrum disorder (ASD). Currently, there are
no drugs approved for treating the core symptoms of ASD.
More broadly, the trial findings support the “cell danger response
theory,” which posits that autism and other chronic conditions are
fundamentally driven by metabolic dysfunction—and thus treatable.
Naviaux and his co-authors propose larger, longer clinical trials
to assess suramin (or similar drugs) as an ASD treatment.
Special note from the researchers: Suramin is not approved for the
treatment of autism. Like many intravenous drugs, when
administered improperly by untrained personnel, at the wrong dose
and schedule, without careful measurement of drug levels and
monitoring for toxicity, suramin can cause harm. Careful clinical
trials will be needed over several years at several sites to learn
how to use low-dose suramin safely in autism, and to identify
drug-drug interactions and rare side effects that cannot currently
be predicted. We strongly caution against the unauthorized use of
Q&A: Suramin Autism Treatment-1
Interview with Robert Naviaux, MD, PhD, professor of genetics
in the departments of medicine, pediatrics and pathology
QUESTION: What is the main point of your paper?
ANSWER: The first thing you need to know about our paper is
that it is not about suramin. Our research is aimed at
finding a unifying cause for autism and an explanation for why it,
and nearly 20 other chronic diseases, have been increasing over
the past 30 years. Our research is leading us to the
conclusion that autism is caused by a treatable metabolic syndrome
in many children. The exact percentage is currently unknown.
Metabolism is the language the brain, gut and immune system use to
communicate. These three systems are linked. You can't change one
without changing the other. Each of these systems works
differently in autism, but more specifically, the communication
between these systems is changed in autism. Such changes
occur both during and after the pregnancy. Suramin can only
improve metabolic functions once a child is treated. While
antipurinergic therapy (APT) with suramin may not directly change
some aspects of abnormal brain development that were present
before treatment, APT may improve the function of many brain
systems, even if brain structure does not change. And in children
and teens whose brains are still developing, the course or
trajectory of brain development might also be changed by
The metabolic syndrome that underlies the dysfunction is caused by
the abnormal persistence of the cell danger response or CDR.
Aspects of the CDR are also known to scientists as the "integrated
stress response." Both genes and environment contribute to the
CDR, so even genetic causes of autism lower the threshold for CDR
activation and produce the metabolic syndrome. Ultimately, if the
symptoms of autism are caused by a metabolic syndrome, the hopeful
message is that the symptoms can be treated, even though we can't
change the genes.
QUESTION:What can you say about the study for neuroscientists and
families who have never heard of the cell danger response or
ANSWER: The main conclusions from the study do not require any
background knowledge. Although the study was small and
preliminary, the main conclusions were three: 1) For many
children, the symptoms of autism are not fixed and can be improved
dramatically with the right treatment; 2) A treatable metabolic
syndrome contributes to the pathogenesis of core symptoms of
autism and 3) A single treatment with low-dose suramin was safe
and produced significant improvements in the core symptoms and
metabolism associated with ASD.
QUESTION: What are the caveats?
ANSWER: After summarizing the design and results of the
study, we are left with the conclusion that either the results are
wrong because of the small size of the study, or they are an
important advance. We won't know which until the results can
be replicated in larger studies. Even so, I am optimistic
that we are on the right path. My hope is that other
investigators will soon join in. Together we can all move
faster to prove or disprove the CDR hypothesis and test the safety
and efficacy of antipurinergic therapy in autism.
QUESTION. What exactly is the cell danger response (CDR)?
ANSWER: The CDR is a natural and universal cellular response
to any injury or stress. Its purpose is to help protect the
cell and to jump-start the healing process. But sometimes
the CDR gets stuck. This prevents completion of the natural
healing cycle and can permanently alter the way the cell responds
to the world. When this happens, cells behave as if they are
still injured or in imminent danger, even though the original
cause of the injury or threat has passed. On a molecular
level, the defended set points for cellular homeostasis are
altered. This creates a pathological metabolic memory—an abnormal
cellular response—that leads to chronic disease. When this happens
during early child development, it causes autism and many other
chronic childhood disorders. When it happens later in life,
a persistent CDR can lead to immune exhaustion and it can lower
the resistance to chronic infections. When it swings in the
other direction, the immune system takes on a hair trigger and it
leads to inflammatory and autoimmune disorders. In both
cases, it increases the prevalence of chronic disease.
QUESTION: How is purinergic signaling connected to the
ANSWER: In a second discovery from the lab, we found that
extracellular nucleotide signaling called "purinergic signaling"
maintains the CDR. This led us to the possibility of a unified
approach to the treatment of autism. Antipurinergic drugs
can treat the abnormal metabolic syndrome that causes autism by
sending a cellular "all's clear" or safety signal like the one
that is announced when a fire is extinguished, telling you it is
safe to return to school. Suramin is just the oldest
antipurinergic drug available, and the only one that inhibits the
particular purinergic receptors that cause autism. Many more
antipurinergic drugs are in development. Suramin is just the
first of a whole new class of medicines, like the first statin for
high cholesterol or the first beta blocker for high blood
QUESTION: How does suramin work?
ANSWER: Pharmacologically, suramin has several actions. One
of its best-studied actions is as an inhibitor of purinergic
signaling. Inside the cell, nucleotides like ATP and UTP are
energy carriers and important molecules in normal metabolism.
Stressed cells release ATP and other molecules made by
mitochondria into the extracellular space through channels in the
cell membrane. Extracellular ATP (eATP) is an ancient danger
signal. It is called a "damage associated molecular pattern"
or DAMP. When too much eATP is released, it binds to
purinergic receptors and activates the CDR. Suramin inhibits
the binding of eATP and eADP to these receptors and sends the
cellular equivalent of the "all's clear" or safety signal.
In this capacity, suramin and other antipurinergic drugs are a
kind of molecular armistice therapy, signaling the cellular war is
over, the danger has passed and cells can return to "peacetime"
jobs like normal neurodevelopment, growth, and healing.
Clinically, suramin works by removing negative signals that block
or slow natural child development. It is more like removing
the brakes then pressing the accelerator. Accelerated
catch-up development occurs in the first few weeks when the brakes
are removed because the child is ready to develop, but was
otherwise blocked by their illness. This reminds me of giving a
child who has an inborn error of metabolism in a vitamin or
nutrient that they can't make or taking away a toxin. The children
begin to blossom. Children with severe oral motor dyspraxia
in the SAT-1 study started humming and singing nonsense tunes
around the house in the first few days after suramin. Like a
baby learning to talk for the first time, they began making new
sounds with their mouth, lips and tongue that they had never made
before. We had four non-verbal children in the study, two
6-year-olds and the two 14-year-olds. The 6- and the
14-year-old who received suramin said the first sentences of their
lives about one week after the single suramin infusion. This
did not happen in any of the children given placebo.
QUESTION: How many purinergic receptors are there?
ANSWER: There are 19 different purinergic receptors.
Geoff Burnstock (University College London) discovered purinergic
signaling in 1972, and has been characterizing the nucleotide and
nucleoside ligands, their receptors and their biology ever since.
QUESTION: What about the side effects of suramin?
ANSWER: We did not find any serious side effects or safety
concerns in this first study of a single, low-dose of
suramin. The low dose that we used produced blood levels of
5-15 µM and has never been tested for any disease in the nearly
100 years that suramin has been used in medicine. All
previous uses of suramin have been at medium doses for sleeping
sickness that produced blood levels of 50-100 µM for one to three
months or high doses for cancer chemotherapy that produced blood
levels of 150-270 µM for three to six months.
It is important to remember that our study was small and only five
boys received suramin. We were unable to detect rare side effects
that might affect fewer than twenty percent (1 in 5) patients.
Suramin caused a self-limited, asymptomatic rash, but this
disappeared without treatment in two to four days. Larger
clinical trials will be needed to detect uncommon side
effects. For example, a study in which at least 100 children
received suramin would be necessary to detect a side effect that
occurred in just one out of 100 (1 percent) of children.
QUESTION: What about the risk of infections? If
suramin blocks the CDR, won't children have trouble clearing
common infections or responding to toxin exposures?
ANSWER: In theory, this could be a risk of suramin.
However, we looked at this carefully in the trial. The
infusions were done from October through February, so winter colds
were a known risk. We found that two children in the placebo
group got colds. Two children in the suramin group also had
colds. The severity was the same in both groups. The
duration of congestion and symptoms was seven to 10 days, and also
about the same in both groups. We did not find an increased risk
of infection in the SAT-1 study. However, in theory, any
broad-spectrum antipurinergic drug might inhibit the CDR so this
will be a potential risk to monitor in future studies.
QUESTION: What problems can you imagine that might derail
future suramin trials in autism?
ANSWER: If the improvements that occurred with suramin
treatment stopped after a few months, even when effective blood
levels were maintained, then the trials would fail. Also, if
we encountered a safety issue that was unacceptable after a few
months of treatment, then the trials might fail.
Even if suramin itself is not the best antipurinergic drug for
autism, our studies have helped blaze the trail for the
development of new antipurinergic drugs that might be even
better. Before our work, no one knew that purinergic
signaling abnormalities were a part of autism. Now we do,
and new drugs can be developed rationally and systematically.
QUESTION: Will suramin need to be given for life?
ANSWER: I don't think so, but we don't have the science to
answer this question yet. More studies will be necessary to
see if improved development can become self-sustaining without the
need for regular suramin treatment.
QUESTION: What about the effect that suramin might have on
ANSWER: We found that during the time the children were on
suramin, the benefit from all their usual therapies and enrichment
programs increased dramatically. Once suramin removed the
roadblocks to development, the benefit from speech therapy,
occupational therapy, applied behavior analysis and even from
playing games with other children during recess at school
skyrocketed. Suramin was synergistic with their other
QUESTION: Why was your study so small?
ANSWER: This work is new and this type of clinical trial is
expensive. We did not have enough funding to do a larger study.
And even with the funding we were able to raise, we had to go
$500,000 in debt to complete the SAT-1 trial. Fortunately,
the goals of establishing basic safety, tolerability and activity
of suramin in autism were accomplished with just 10 subjects.
Based on these initial promising results, we will now attempt to
find funding for a larger trial.
QUESTION: What is the rate-limiting factor to progress right now?
Where are the bottlenecks?
ANSWER: The rate-limiting factor is money. Lack of funding
has slowed our research progress on the CDR and purinergic
signaling in autism for the past nine years. We can't do the
next studies without new funding. We have plans for five
additional studies over the next five years to collect all the
data the FDA will need to decide about the approval of suramin for
autism. With adequate funding, culminating in a multicenter,
phase III, registrational trial, these studies can be completed
without further delay. Usually, the multimillion dollar cost of
new drug development is covered by the Big Pharma that will
benefit from FDA approval. Unfortunately, since suramin is
100 years old, the usual patent laws don't apply and the next
clinical trials will require grass roots support from families and
foundations and other approaches to raise the needed funding.
There's more information at our website:
QUESTION: Do you think that suramin could help the genetic
causes of autism too? Why?
ANSWER: Yes. Each of the genes that increase the risk
of autism is connected to the cell danger response. For example,
the Fragile X gene naturally prevents the translation of a large
number of pro-inflammatory proteins. When the Fragile X gene
is mutant, pro-inflammatory proteins like TNF-alpha and IL1-beta
are made, which activates the CDR. The causal gene in
Angelman syndrome is thought to be the ubiquitin protein ligase
E3A (UBE3A). When this gene is not expressed, worn-out
proteins in the cell are not removed properly. This triggers
the unfolded protein response, which activates the CDR. The
causal gene in Smith-Magenis syndrome is thought to be the
retinoic acid activated gene 1 (RAI), which is needed for a normal
antiviral response. Failure to express RAI prevents normal
handling of infections and results in a persistently activated
CDR. We don't think that suramin will treat the physical
features and non-autism symptoms of these genetic disorders.
However, we think that suramin will be effective in improving the
core symptoms of autism in these genetic disorders, and produce
improvements in language, social behavior, and decrease repetitive
and restricted behaviors.
QUESTION: What about teens and adults with ASD who don't want to
be treated but rather want to be accepted and appreciated for
their unique talents, abilities, and differences?
ANSWER: ASD is a label we use to talk about a group of children
and adults with a recognizable pattern of neurodevelopmental
differences. In the extreme, some non-verbal children with
ASD will grow up to be non-verbal adults who cannot speak for
themselves and may not ever be able to care for their own daily
needs or hold down jobs.
In the other extreme, the special gifts of some children with ASD
will lead them to become activists as teens and adults whose
voices are highly sought out by local and national agencies to
express the needs of others and to help guide progress. We had a
gifted teen with ASD as part of the team on the SAT1 study.
He is a graphic artist and helped us to design the storyboards
that allowed each parent and their child to visually review and
prepare for the steps of the study, with special attention to
sensory issues that were important for children with ASD.
I have no desire to create new treatments for anyone who does not
need or want treatment. I do not want to eliminate any
symptoms or special gifts that someone wants to keep. The right to
self-determination and the right to health care choice are
fundamental freedoms. However, unless research can continue
with the goal of helping children and adults who want treatment,
new treatments will not be discovered and the complementary
freedom to choose a treatment when it is desired will be
lost. We can respect both rights: the right to choose no
treatment for some and the right to choose new treatments for
others. Both are possible, and both must be actively chosen to
protect freedoms for all.
There is another point that needs to be made. In 2017, after more
than 70 years of trying, there are no effective pharmacologic
treatments for the core symptoms of autism because a unifying
theory for the cause of autism does not exist. People's experience
with ASD treatments-to-date have taught them that the treatment is
often worse than the disorder. None of the treatments currently
available actually get at the root problem in autism. If the root
problem is ultimately proven to be the CDR and abnormalities in
purinergic signaling, then the core symptoms like social fear,
anxiety and difficulties with verbal communication might be
improved without suppressing the gifts that make children and
adults with ASD exceptional. This new generation of treatments has
a chance to precisely target the symptoms that hold people back
with ASD, while not touching the gifts that allow them to excel.
QUESTION: Why is treating autism so important?
ANSWER: Autism spectrum disorder often affects children who have
shown early gifts, and might otherwise grow up to become some of
the best and brightest of their generation. Even if this is
only true for a fraction of children, it means that some children
now living with disabling forms of ASD, whose parents fear they
might never be able to live independently, could have a chance for
independence and live happy, self-reliant lives. And because
many children with ASD are significantly impacted by their
symptoms, these children, once freed from their most disabling
symptoms, might be just the ones the world needs to solve the
greatest problems facing our planet in the next century.
Antipurinergic Therapy with Suramin as a Treatment for Autism
Rafie Hamidpour, et al.
Dr. Rafie Hamidpour
Pars Bioscience, LLC, 14109 Cambridge Lane
Leawood, Kansas 66224, USA
Tel: (913) 432-0107
Fax: (913) 432-5708
Trade names : Antrypol, 309 Fourneau, Bayer 205, others
Routes of administration : by injection only
ATC code P01CX02 (WHO) QP51AE02 (WHO)
Legal status: US: not FDA approved
CAS Number : 145-63-1 ☑
ECHA InfoCard 100.005.145 Edit this at Wikidata
Chemical and physical data
Molar mass : 1297.26 g·mol−1
Suramin is a medication used to treat African sleeping sickness
and river blindness. It is the treatment of choice for
sleeping sickness without central nervous system involvement.
It is given by injection into a vein.
Suramin causes a fair number of side effects. Common side
effects include nausea, vomiting, diarrhea, headache, skin
tingling, and weakness. Sore palms of the hands and soles of
the feet, trouble seeing, fever, and abdominal pain may also
occur. Severe side effects may include low blood pressure,
decreased level of consciousness, kidney problems, and low blood
cell levels. It is unclear if it is safe when breastfeeding.
Suramin was made at least as early as 1916. It is on the World
Health Organization's List of Essential Medicines, the safest and
most effective medicines needed in a health system. In the
United States it can be acquired from the Center for Disease
Control (CDC). The cost of the medication for a course of
treatment is about US$27. In regions of the world where the
disease is common suramin is provided for free by the World Health
Our lab sees autism spectrum disorder (ASD) as an involuntary
behavioral syndrome caused by a conserved cellular response to
environmental and genetic danger. Autism is therefore
an “ecogenetic” syndrome that alters child development. This
perspective has led us to a unified theory for the cause and
treatment of ASD that is called the cell danger theory1-7. It
proposes that autism is a treatable metabolic syndrome caused by
persistent activation of the cell danger response (CDR) produced
by persistent abnormalities in purinergic signaling.
By treating the root cause of this syndrome, we believe many
children will have chance to lose the symptoms that hold them
back. Many children will be able to come off spectrum, and many
children will be able to live independent lives as adults, when
just a few years ago this notion seemed impossible...
DIAGNOSTIC AND METHODS OF TREATMENT FOR CHRONIC FATIGUE
SYNDROME AND AUTISM SPECTRUM DISORDERS
[ PDF ]
The disclosure relates to biomarkers useful for diagnosing and
predicting the development of chronic fatigue syndrome (CFS). The
disclosure further provides methods to reset metabolism and
facilitate healing in CFS patients by administering antipurinergic
METHODS FOR AUTISM SPECTRUM DISORDER PHARMACOTHERAPY
[ PDF ]
Disclosed herein are compositions of antipurinergic agents and
methods of use thereof for treating cognitive developmental
disorders and autism spectrum disorders (ASD) in patients in need
Methods of treatment of mitochondrial disorders
[ PDF ]
In accordance with the present invention, there are provided
methods for the treatment of mitochondrial disorders. Invention
methods include the administration of a pyrimidine-based
nucleoside such as triacetyluridine, or the like. Also provided
are methods of reducing or eliminating symptoms associated with
mitochondrial disorders. Mitochondrial disorders particularly
appropriate for treatment include those attributable to a
deficiency of one or more pyrimidines.
Pharmacokinetics of single-dose suramin in
children with autism ...
PLoS One. 2013;8(3):e57380. doi:
10.1371/journal.pone.0057380. Epub 2013 Mar 13.
Antipurinergic therapy corrects the
autism-like features in the poly(IC) mouse model.
Naviaux RK, et al.
BACKGROUND: Autism spectrum disorders (ASDs) are caused by both
genetic and environmental factors. Mitochondria act to connect
genes and environment by regulating gene-encoded metabolic
networks according to changes in the chemistry of the cell and its
environment. Mitochondrial ATP and other metabolites are
mitokines-signaling molecules made in mitochondria-that undergo
regulated release from cells to communicate cellular health and
danger to neighboring cells via purinergic signaling. The role of
purinergic signaling has not yet been explored in autism spectrum
OBJECTIVES AND METHODS: We used the maternal immune activation
(MIA) mouse model of gestational poly(IC) exposure and treatment
with the non-selective purinergic antagonist suramin to test the
role of purinergic signaling in C57BL/6J mice.
RESULTS: We found that antipurinergic therapy (APT) corrected 16
multisystem abnormalities that defined the ASD-like phenotype in
this model. These included correction of the core social deficits
and sensorimotor coordination abnormalities, prevention of
cerebellar Purkinje cell loss, correction of the ultrastructural
synaptic dysmorphology, and correction of the hypothermia,
metabolic, mitochondrial, P2Y2 and P2X7 purinergic receptor
expression, and ERK1/2 and CAMKII signal transduction
CONCLUSIONS: Hyperpurinergia is a fundamental and treatable
feature of the multisystem abnormalities in the poly(IC) mouse
model of autism spectrum disorders. Antipurinergic therapy
provides a new tool for refining current concepts of pathogenesis
in autism and related spectrum disorders, and represents a fresh
path forward for new drug development.
Mol Autism. 2015 Jan 13;6:1.
Antipurinergic therapy corrects the
autism-like features in the Fragile X (Fmr1 knockout) mouse
Naviaux JC, et al.
BACKGROUND: This study was designed to test a new approach to
drug treatment of autism spectrum disorders (ASDs) in the Fragile
X (Fmr1) knockout mouse model.
METHODS: We used behavioral analysis, mass spectrometry,
metabolomics, electron microscopy, and western analysis to test
the hypothesis that the disturbances in social behavior, novelty
preference, metabolism, and synapse structure are treatable with
antipurinergic therapy (APT).
RESULTS: Weekly treatment with the purinergic antagonist suramin
(20 mg/kg intraperitoneally), started at 9 weeks of age, restored
normal social behavior, and improved metabolism, and brain
synaptosomal structure. Abnormalities in synaptosomal glutamate,
endocannabinoid, purinergic, and IP3 receptor expression,
complement C1q, TDP43, and amyloid β precursor protein (APP) were
corrected. Comprehensive metabolomic analysis identified 20
biochemical pathways associated with symptom improvements.
Seventeen pathways were shared with human ASD, and 11 were shared
with the maternal immune activation (MIA) model of ASD. These
metabolic pathways were previously identified as functionally
related mediators of the evolutionarily conserved cell danger
CONCLUSIONS: The data show that antipurinergic therapy improves
the multisystem, ASD-like features of both the environmental MIA,
and the genetic Fragile X models. These abnormalities appeared to
be traceable to mitochondria and regulated by purinergic
Transl Psychiatry. 2014 Jun 17;4:e400.
Reversal of autism-like behaviors and
metabolism in adult m
ice with single-dose antipurinergic therapy.
Naviaux JC, et al.
Autism spectrum disorders (ASDs) now affect 1-2% of the
children born in the United States. Hundreds of genetic, metabolic
and environmental factors are known to increase the risk of ASD.
Similar factors are known to influence the risk of schizophrenia
and bipolar disorder; however, a unifying mechanistic explanation
has remained elusive. Here we used the maternal immune activation
(MIA) mouse model of neurodevelopmental and neuropsychiatric
disorders to study the effects of a single dose of the
antipurinergic drug suramin on the behavior and metabolism of
adult animals. We found that disturbances in social behavior,
novelty preference and metabolism are not permanent but are
treatable with antipurinergic therapy (APT) in this model of ASD
and schizophrenia. A single dose of suramin (20 mg kg(-1)
intraperitoneally (i.p.)) given to 6-month-old adults restored
normal social behavior, novelty preference and metabolism.
Comprehensive metabolomic analysis identified purine metabolism as
the key regulatory pathway. Correction of purine metabolism
normalized 17 of 18 metabolic pathways that were disturbed in the
MIA model. Two days after treatment, the suramin concentration in
the plasma and brainstem was 7.64 μM pmol μl(-1) (±0.50) and
5.15 pmol mg(-1) (±0.49), respectively. These data show good
uptake of suramin into the central nervous system at the level of
the brainstem. Most of the improvements associated with APT were
lost after 5 weeks of drug washout, consistent with the 1-week
plasma half-life of suramin in mice. Our results show that purine
metabolism is a master regulator of behavior and metabolism in the
MIA model, and that single-dose APT with suramin acutely reverses
these abnormalities, even in adults.
Mitochondrion. 2018 Nov;43:1-15.
Antipurinergic therapy for autism-An
Are the symptoms of autism caused by a treatable metabolic
syndrome that traces to the abnormal persistence of a normal,
alternative functional state of mitochondria? A small clinical
trial published in 2017 suggests this is possible. Based on a new
unifying theory of pathogenesis for autism called the cell danger
response (CDR) hypothesis, this study of 10 boys, ages 5-14years,
showed that all 5 boys who received antipurinergic therapy (APT)
with a single intravenous dose of suramin experienced improvements
in all the core symptoms of autism that lasted for 5-8weeks.
Language, social interaction, restricted interests, and repetitive
movements all improved. Two children who were non-verbal spoke
their first sentences. None of these improvements were observed in
the placebo group. Larger and longer studies are needed to confirm
this promising discovery. This review introduces the concept of M2
(anti-inflammatory) and M1 (pro-inflammatory) mitochondria that
are polarized along a functional continuum according to cell
stress. The pathophysiology of the CDR, the complementary
functions of M1 and M2 mitochondria, relevant gene-environment
interactions, and the metabolic underpinnings of behavior are
discussed as foundation stones for understanding the improvements
in ASD behaviors produced by antipurinergic therapy in this small
A new diamidine salt and process for its preparation
[ PDF ]
The invention comprises the salt of the symmetrical urea of
m-aminobenzoyl-p-methyl-m - aminobenzoyl - 1 - aminonaphthalene-4
: 6 : 8-trisulphonic acid (suramin) and 1 : 5-di - (41 -
amidinophenoxy) pentane uncontaminated with either the acid or the
base from which it may be formed or another salt of said base or
said acid. It can be produced by reacting in aqueous medium a
water-soluble salt of the suramin (e.g. the sodium salt) with a
water-soluble salt, such as the isethionate or methane sulphonate,
of the 1 : 5-di-(41-amidinophenoxy) pentane and isolating from the
reaction medium the diamidine salt thus formed. An example
illustrates this process.
The diamidine salt of this invention is prepared by reaction
together in an aqueous medium a water-soluble salt, for example,
the sodium salt of the symmetrical urea of m-aminobenzoyl-pmethyl
- m - aminobenzoyl - 1 - aminonaphthalene 4:6:8-trisulphonic acid,
which urea is hereinafter referred to by its common name
"suramin," and a water-soluble salt of
1:5-di(4-amidinophenoxy)pentane, for example, the isethionate or
methane sulphonate, and isolating from the reaction mixture the
salt thus formed. The resulting salt is
<RTI>enly</RTI> sparingly soluble in
<RTI>water,</RTI> and is <RTI>conveniently
isolated by crystallisation.
The salt as thus; prepared has been</RTI> proved to bel of
as a therapeutic agent. More particularly, it has been shown to
possess a marked prophylactic and curative effect in the treatment
of trypanosome infections. Both 1:5-di(4-amidinophenoxy)-pentane
and suramin are known to possess in the form of certain
water-soluble salts, such as the isethionate and sodium salts
respectively trypanocidal activity but comparative experiments
have demonstrated the fact (which is all the more surprising in
view of the low solubility of the suramin salt of the diamidine)
that the new salt is unexpectedly and substantially superior to
either. Thus, in parallel toxicity experiments in rats to
determine the maximum non-lethal dose on sub-cutaneous
administration, the following figures were obtained:
(a) 1:5-di(4-amidino-phenoxy-pentane 5 mg./100 g.
(b) suramin - - - - - - - 40 mg./100 g.
(c) the suramin salt of the diamidine > 500 mg./100 g.
The diamidine itself is known to possess a prophylactic action
against rat trypanosomiasis and comparative tests of the diamidine
and the new salt thereof were therefore conducted in this
<RTI>connec</RTI> tion. In these tests the drugs were
administered sub-cutaneously and after definite intervals (1, 2,
4, 8 and 12 weeks) the test animals were inoculated subcutaneously
with the aforesaid strain of T. brucel and the blood examined
every two or three days for a month. If in that period no evidence
of infection was found protection was considered complete. Ubder
these test conditions, it was found that the diamidine at maximum
non-lethal dose (5 mg./100 g.) gave protection for 4 weeks while
the new salt at less than one thirtieth of the maximum non-lethal
dose (15 mg./100 g.) gave protection for at least 8 months.
Further, such <RTI>tests</RTI> in which all three
<RTI>products were compared showed that the</RTI>
maximum doses requireld to give com<RTI>plete</RTI>
protection for a period of 4 <RTI>weeks</RTI> were 5
mg./100 g. in the case of the diamidine, 2 mg/100 g. in the case
of suramin and 1.96 mg./100 g. of the new salt containing 0.7 mg.
of the diamidine <RTI>and O.S mg. of surarain.</RTI>
The <RTI>production</RTI> of the
<RTI>new</RTI> salt is illustrated in tbe following
To a solution of suramin sodium (14.3 g.) in water (30 c.c.) is
added a solution of 1:5 - di(4-amidinophenoxy)-pentane
methane-sulphonate in water (300 c.c.) at 45 C. A white
precipitate forms which is left to stand overnight and is then
filtered off, washed with water (150 c.c.) and dried at 50 C.
under 12 mm. of mercury. The suramin salt of
1:5di(4-amidinophenoxy)-pentane (26 g.) is thus obtained which
crystallises with 30 molecules of water.
We are aware that Guimares and Lourie, British Journal of
Pharmacology and Chemotherapy (1951) Vol. 6, pages 514 to 530,
have referred to the fact that a precipitate is liable to form in
mixtures of dilute solutions of suramin and
1:5-di(4-amidinophenoxy)pentanealso known as pentamidine and give
reasons for attributing to the formation of an inactive salt
complex the inhibitory effect observed by them in respect of a
previous injection of suramin (or the presence of suramin) on
certain actions of pentamidine, viz, fall of blood pressure,
broncho-constriction, contraction of gut, " curare-like " action
on the rat phrenic nerve diaphragm preparation, paralysis in frogs
and toxicity for mice.
Improvements in or relating to heterocyclic compounds
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This invention is for improvements in or relating to
phenanthridinium salts and to processes for their production, and
has for its object the provision of new and therapeutically useful
While many phenanthridine compounds, in the form of their
quaternary salts, have heretofore been proposed for use as
trypanocidal agents, only a few have been used to any substantial
extent in the field. Not only degree of activity but also toxicity
vary markedly with change in the number and nature of substituents
and it is impossible at the present time to predict a priori the
properties (if any) of any new phenanthridine compound.
As a result of research and experimentation, the present
Applicants have prepared new phenanthridinium salts which have a
high activity against blood parasites, such as trypanosomes, are
surprisingly less toxic than Inown phenanthridinium salts
possessing useful trypanocidal activity and, in consequence,
exhibit an exceptionally high chemotherapeutic index.
The marked utility of the new compounds is manifested not only in
the treatment of trypanosome infections but also in relation to
According to a further feature of the invention, those salts of
formula I in which R1 represents a hydrogen atom or a m
amidinophenyldiazoamino group, may be prepared by diazotizing or
tetrazctizing a phenanthridinium salt of formula II wherein R is a
hydrogen atom or an amino group and coupling the resultant
diazonium or bisdiazonium salt with m-aminobenzamidine,
The invention is illustrated by the following Examples, in which
the temperatures stated were measured in degrees Centigrade.
A solution of m-aminobenzamidine monohydrochloride dihydrate (51.9
g.) in water (225 ml.) and concentrated hydrochloric acid (56.5
ml.) was cooled to 0 and diazotised with sodium nitrite (17.6 g.)
in water (100 ml.) any excess nitrous acid remaining being
decomposed by the addition of sulphamic acid. The diazonium
solution was added to a solution of 2:7 - diamino - 10 -
ethyl9-phenylphenanthridinium chloride (99.5 g.) in water (600
ml.) at 00. To the stirred mixture, an ice-cold solution of sodium
acetate (142.5 g.) in water (450 ml.) was added.
Stirring was continued at 0 for 75 minutes and then a further
quantity of sodium acetate (61.5 g.) together with sodium chloride
(45 g.) dissolved in ice-cold water (450 ml.) was added. After 45
minutes the product was precipitated as a purple tar by the
addition of saturated brine (600 ml.). The supernatant liquors
were decanted. The purple residue was dissolved in water (1 1.)
and reprecipitated with brine (500 ml.). Paper electrophoresis of
the precipitated tar (No.1 Whatman paper" Whatman" is a Registered
Trade Mark) in 3N acetic acid showed the presence of two main
components, the more mobile one giving a purple spot, the less
mobile one giving a yellow spot. Subsequent purification steps
were followed by paper electrophoresis; the purple isomer isolated
was found to correspond to the purple spot and the red isomer to
the yellow spot.
The presence of traces of unchanged 2:7 diamino - 10 - ethyl - 9 -
phenylphenanthrdinium chloride in the unpurified reaction product
was indicated, on paper electrophoresis, by the presence of a
characteristic orange spot. The foregoing precipitated tar was
dissolved in boiling water (300 ml.) andthe solution rapidly
cooled. The solid A which separated on standing in the
refrigerator overnight was filtered off from the liquors R. On
crystallisation of the solid A by dissolving it in boiling water
and rapidly cooling the solution purple prisms, m.p. 258260
(decomp.) were obtained.
To the liquors B, obtained as described above, saturated sodium
bromide solution was added. The solid precipitate (60 g.) was
washed with acetone and extracted with cold methanol (5 x 100 ml.)
to leave a red residue (24.3 g., 15.5%) which was shown by paper
electrophoresis to be an almost pure product. Crystallisation of
this product from methanol gave 7 - (m - amidinophenyl diazeamino)
- 2 - amino - 10 - ethyl-9-phenyl- phenanthridinium bromide
hydrobromide as red needles, m.p. 2400 (decomp.).
This bromide hydrobromide salt (1 g.) in methanol (700 ml.) was
converted to the corresponding chloride hydrochloride by ion
exchange through a column of Axnberlite IRA 400 ("Arnberlite" is a
Registered Trade Mark) chloride resin. 7 - (m - Amidino
phenyldiazoamino) - 2 - amino - 10 - ethyl 9 -
phenylphenanthridinium chloride hydro chloride was obtained as red
Phenanthridinium salts and their preparation
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The invention comprises: (a)
amidinophenyldiazoaminophenanthridinium salts of the general
formula (wherein Am represents -C(:NH)NH2, R1 a C1-6 alkyl group,
R2 an aryl group, R3 a C1-6 alkoxy group or a halogen atom and Y a
pharmaceutically acceptable anion) and their acid addition salts
(including insoluble salts, e.g. amsonates, embonates and suramin
salts); (b) the preparation of compounds I, in admixture with
isomeric azo dyestuffs (see Group IV(c)) from which they may or
may not be separated, by diazotizing a compound of the general
formula and coupling the resulting diazonium salt with an
equimolecular proportion of a phenanthridinium salt of the general
formula and (c) pharmaceutical compositions comprising at least
one compound I, with or without the isomeric azo dyestuff, in
association with a significant amount of a pharmaceutical carrier.
Compounds I can also be prepared by diazotizing a compound III and
coupling the resulting diazonium salt with a compound II. The
pharmaceutical compositions, which are active against blood
parasites, e.g. trypano somes, may be in forms suitable for
parenteral or oral administration, e.g. solutions, suspensions,
emulsions, tablets, pills, dispersible powders, granules, syrups,
elixirs and capsules. 4 - Amino-3-bromobenzamidine
monohydrochloride, 3-amino - 4 - chlorobenzamidine dihydrochloride
and 3-amino-4-methoxybenzamidine dihydrochloride are prepared from
the correspondingly substituted benzonitriles.
3-Amino-4-chlorobenzonitrile is prepared by reducing
4-chloro-3-nitrobenzonitrile.ALSO:Azo dyestuffs of the general
formula (wherein R1 represents a C1-6 alkyl group, R2 represents
an aryl group, Y represents an anion, one Z represents the group
and the others hydrogen atoms, Am represents -C(:NH)NH2 and R3
represents a C1-6 alkoxy group or a halogen atom) are obtained as
by-products in the preparation of diazoamino compounds (see Group
IV(b)) by diazotizing a compound of the general formula and
coupling the resulting diazonium salt with an equimolecular
proportion of a phenanthridinium salt of the general formula The
two products may be separated by, for example, fractional
crystallization from methanol.