Memorandum submitted by Professor Malcolm
Hooper, Scientific Advisor to the Gulf Veterans' Association
NERVE AGENT PRE-TREATMENT SETS (NAPS)—PYRIDOSTIGMINE
BROMIDE, PB
Pyridostigmine bromide, an old drug patented
in 1951, is used almost exclusively for the treatment of Myasthenia
gravis, an autoimmune disease, in which acetylcholine receptors
in muscle, Figure 4, are progressively destroyed. It acts as a
reversible inhibitor of acetylcholinesterase, AchE, an enzyme
which destroys acetylcholine, Ach. Inhibition of AchE increases
the level of Ach at the nerve-muscle junction and compensates,
in the early stages of Myasthenia gravis, for the loss
of the receptors which are responsible for onward transmission
of the nerve impulse.
PB was subsequently investigated in animal studies
as a protective agent against the nerve agent soman. This point
is important on two counts—
1. Soman and related, organophosphate nerve
agents, sarin, cyclosarin, VX are potent irreversible inhibitors
of AchE. Irreversible inhibitors act over a long time and their
effects are only overcome by the synthesis of new enzyme which
takes days. To avoid total loss of AchE it was necessary to—
(a) find new drugs, which would need to be
administered as soon as a chemical attack occurred, that would
displace the nerve agents from their binding sites on AchE. Such
a drug is pralidoxime, P2S. It was provided in "combopens"
issued to the troops. [These also contained atropine, a potent
anti-muscarinic drug, and avizafone, a pro-drug of diazepam see
CWs below.]
(b) protect AchE by prior treatment, ie prophylactically,
using a compound that prevents binding of the nerve agent to AchE.
2. Soman is particularly dangerous in that
it "ages" AchE very rapidly and renders the enzyme insensitive
to rescue by pralidoxime.
It was proposed that pyridostigmine bromide
by binding reversibly would prevent the binding of soman to AchE.
This would result in the gradual release of undamaged enzyme,
as the PB-AchE complex dissociated, restoring a limited amount
of normal function, Figure 6.
Approximately 30 per cent of AchE is inactivated
by the reversible binding of PB. When the drug is no longer at
the calculated blood level the bound complex slowly dissociates
restoring AchE levels to normal.
An attack involving soman would lead to all
the AchE being inhibited but slowly the AchE-PB complex would
dissociate, if no further PB was taken, liberating free enzyme
to restore some nerve function. However, administering PB whilst
being exposed to any nerve agent would exacerbate and not relieve
the symptoms/damage.
Such a strategy required two important judgements
to be made—
(i) How much enzyme could be inhibited by
PB without compromising the ability of troops to engage in warfare?
(ii) Which sites within the body needed to
be protected?
This was completely new territory. No experimental
data from human studies were available. The strategy was unproven.
The use of PB would be experimental.
THE TROOPS WOULD BE USED AS GUINEA PIGS
It was decided to use a dose of PB, 30 mg eight-hourly,
that would bind to 30 per cent of AchE. It was further assumed
that PB, a quaternary compound would not enter the brain.
The strategy is fatally flawed—see also
CWs antidotes and treatment, below.
If PB did not enter the brain then it would
only protect AchE in the periphery and not in the brain! Any restoration
of function would only be possible in the periphery. The recovery
of battlefield casualties would be very unpredictable. They might
die from the centrally mediate effects of nerve agents or survive
as human "vegetables".
As for the assumptions. All the reports from
troops taking PB describe the classic textbook symptoms of increased
cholinergic stimulation—excessive sweating, lacrimation,
salivary secretion, increased need to micturate and defaecate,
lowered heart rate and force, respiratory problems from increased
secretions, loss of muscle power, and disturbances of eyes, and
the central nervous system.
It has now been demonstrated in experimental
animals that the blood-brain barrier is breached when animals
are stressed. Under these conditions PB might enter the brain.
Increased central cholinergic effects have been found in troops,
Sharabi et al, 1991 taking PB and in experimental stressed
animals following administration of PB, Friedman et al,
1996, Kaufer et al, 1998.
There is considerable evidence of synergistic
adverse effects arising from interactions between PB, OPs, DEET
and permethrin which affect the entire nervous system, see Golomb,
1999 for a comprehensive review. This evidence appears in peer
reviewed papers, several reports from the USA Congress, House
of Representatives, and the final Presidential Commission.
In addition adverse synergistic interactions
involving the cholinergic and the-adrenergic stress-response system
have been reported, Chaney, 1997; Moss, 1998, 1999.
The recent Rand Report, Golomb, 1999, which
includes 83 pages of references, concluded that,
(1) PB cannot be ruled out as a possible
contributor to the development of unexplained or undiagnosed illness
in some PGW (Persian Gulf War) veterans . . .
(2) Uncertainties remain concerning the effectiveness
of PB in protection of humans against nerve agents . . .
(3) The use of PB may reduce somewhat the
effectiveness of postexposure treatment for nonsoman nerve agents
. . .
(4) The issue is a complex one, involving
trading off uncertain health risks—but risks now shown to
be biologically plausible—against uncertain gains from the
use of PB in the warfare setting.
These rather cautious conclusions can be considerably
strengthened in the light of the work assesed in the whole report
and from consideration of related literature, particularly that
concerning chronic exposure to insecticides and nerve agents.
Haley, 1997a, has found an association of PB
with his Syndromes 2 (confusion ataxia) and 3 (arthro-myo-neuropathy).
CONCLUSION
My overall assessment of the evidence is that
the choice of PB and its proposed use in the Gulf War was—
(1) An unproven strategy involving the use
of troops as experimental subjects without their prior consent.
(2) The strategy was fatally flawed in that
it will not protect the brain from exposure to nerve agents.
(3) The protocol adapted was based on two
assumptions, on dosage and drug distribution, which later proved
to be wrong.
(4) The synergistic adverse interactions
between PB and other anticholinesterase drugs, particularly OP
and carbamate insecticides, greatly exacerbated the injury to
the central, peripheral, and autonomic nervous systems.
(5) The damage referred to in (4) above must
be evaluated in the light of the growing knowledge of the chronic
damage now recognised in OP poisoned animals, sheep farmers, and
pesticide operatives.
(6) It is a shameful fact that there have
been no studies, almost 10 years after the Gulf War, carried out
in the UK which address these health issues despite irrefutable
evidence from studies in the States.
(7) There is clear evidence that there is
a toxic synergism between PB and adrenergic agents, caffeine,
and stress, Chaney et al, 1997; Moss, 1999; and with insecticides,
McCain et al, 1997.
(8) Opioid-cholinergic modulation of growth
hormone, a major endocrine hormone, also occurs with PB, De Marinis
et al, 1997.
(9) Acetylcholine also exerts an effect on
the immune system which would be amplified by PB, Kuby, 1992.
(10) PB alters muscle sensitivity, Lintern
et al, 1997; alters growth hormone responses, Nooitgedagt,
1997; especially in panic attack patients, Cooney et al,
1997.
(11) Causes severe damage in heart muscle
probably by harmful effects on mitochondrial function, Glass et
al, 1996, 1997.
(12) Extensive neurological studies are needed
to evaluate the extent of damage suffered by many veterans. These
must include MRI, SPECT, and PET scans of the brain, studies of
the neuromuscular junction function and peripheral nerve conduction,
assessment of the levels and properties of key enzymes, particularly
paraoxonase, P-450 enzymes, acetylcholinesterases and butyryl
cholinesterases.
NOTE—TAKING
THE TABLETS
It is clear from accounts in the battlefield
that PB tablets were taken erratically. Some troops took 30 mg
three times daily whilst others took 60 mg three times daily.
Some stopped using PB, whilst others increased the dose particularly
when threatened with possible chemical exposures.
VACCINATIONS
The preparation for the Gulf War was done under
considerable pressure and in fear of very heavy casualties. A
vaccination programme was inaugurated in which a large number
of vaccines were given, including those designed to counter the
threat of biological weapons, BWs. Iraq was known to have a large
range of biological cultures for such weapons which were supplied
mainly from the USA, Reigle, 1994, Thomas 1998; see also under
BWs section.
The UK preparation involved the administration
of eight health and hygiene vaccines—typhoid, polio, hepatitis
B, hepatitis A, cholera, tetanus, yellow fever, meningitis, plus
two BW vaccines, anthrax with pertussis (this really is two extra
vaccines and not one), and plague. Botulinum anti-toxin was prepared
in large amounts and sent out to the Gulf to be used if troops
were exposed to botulinum toxin. The Americans received 17 different
vaccines which included additionally influenza, rabies, measles,
Japanese B encephalitis virus, rubella, varicella, and botulinum
toxoid, Specter, 1998.
Although some service personnel did not receive
every one of these vaccines, eg hepatitis A immunoglobulins, it
is generally admitted by the MoD that each soldier received up
to 10 different vaccines.
However, some troops received additional known
vaccines. We have the records of one veteran who received the
controversial MMR, triple vaccine because he had no extant vaccination
records when called up from the reserves.
In addition we know that the vaccination programme
continued in the Gulf and that it was the policy of USA units
to vaccinate everyone in their bases even if they were visiting
Coalition personnel. In this way some UK troops received USA vaccines,
Cammock, 1997.
Both the USA and UK Governments are believed
to have given additional vaccines which were undeclared and unidentified
on grounds of National Security; for example, smallpox and tularaemia
(rabbit fever). Vice-Admiral Revell, the Surgeon General, stated
before the Defence Committee, 1996, that some five or six vaccines
had not been disclosed. A footnote to the report states that what
this meant was five or six injections. Such a statement does not
make sense since he was being asked about vaccines not injections.
I find it difficult to believe that the Surgeon General does not
know the difference between a vaccine and an injection.
Since it is now clearly established that the
USA and UK sold cultures for biological weapons to Iraq we knew
the types of BWs that Iraq might prepare. In this regard, smallpox
is a favoured Russian biological agent (cf soman), and tularaemia
had been developed and weaponised by the USA in 1971-73. Haemorrhagic
viruses, also investigated in the USA as BWs, were released to
Iraq.
RECORDS
It is common knowledge that most of the medical
records detailing the vaccines given have been lost or destroyed.
The destruction of records had been described as a matter of military
policy! In the Lancet paper, by Unwin et al, 1999, some
70 per cent of Gulf personnel were found not to have their records.
It is not possible, therefore, to make any categorical statements
about which vaccines were given and when.
I am aware of Parliamentary reports which list
151 records that the MoD has available. These included two for
smallpox and one for tularaemia. Scaled up to the 53,000 UK personnel.
This equates to about 700 receiving smallpox and 350 tularaemia
vaccinations.
We have some parliamentary answers. Lord Gilbert,
1998, when asked about the smallpox vaccinations replied that
a small number of troops had received smallpox but that he would
not give an exact figure because of issues of National Security.
We have the accounts of the GWVs themselves.
Under oath they are prepared to state that they received smallpox
as part of a larger body of men and that these vaccinations were
not recorded.
The MoD have continued to insist that only two
smallpox vaccinations were given, one by private arrangements,
and the other by mistake! They also insist that the extant, "Rabbit
Fever", vaccination record is a forgery. These explanations
are not satisfactory and in the case of smallpox somewhat contradictory.
WHAT DO
WE KNOW?
It is unequivocally established from the records,
from eye-witnesses, and by tacit admission of the MoD that the
vaccines were administered very hurriedly and in breach of the
normal protocols for vaccination. Some personnel received up to
10 different vaccinations on one day. The vaccination programme
was experimental and given without any informed consent.
MoD memos expressing concern about this situation
have recently been quoted in an exclusive article in the Big Issue
although no such memos have been disclosed to the Independent
Panel established to oversee MoD research programmes in this area.
The use of pertussis with anthrax involved the
unlicensed use of pertussis as an adjuvant which was later shown
not to provide any improvement in the level of antibody response.
This was another experimental procedure, used without informed
consent. It is of grave significance that an, admitted, MoD fax,
which from mice studies indicated that pertussis with anthrax
could have adverse health effects in humans, was not registered
and is now lost. Furthermore, the whole experimental protocol
for this study has also been lost.
The Unwin et al study concluded that
the increased incidence of symptoms amongst UK GWVs was associated
with the vaccines.
Despite all this evidence the MoD/GVIU/MAP continue
to insist that the vaccines were given in accordance with normal
practice and that there were no long term adverse effects from
the vaccination programme (Professor Harry Lee in an address to
the Independent Panel—29 March 1999).
It is clear from research in the states that
the present anthrax vaccine is unproven as an effective treatment
for soldiers exposed to aerosolised spores that would be inhaled.
It is also apparent that only six out of 22 anthrax strains are
effectively neutralised by the present vaccine, Nass 1999. Both
anthrax and pertussis are known to induce autoimmune diseases,
Nass 1999, 1998. The delays in producing a new vaccine and the
continued use of a vaccine, now six years past its approved shelf-life,
are unacceptable and requires much more detailed explanation and
disclosure of the testing data.
I have become aware, through the press, of new
vaccines prepared by Porton Down, against plague, Daily Express
99, again not disclosed to the Panel. A new smallpox vaccine grown
on mammalian tissue has been announced in the USA, American Forces
Press Service, 1999.
Even more disturbing is the Health and Safety
Executive report filed by Porton Down, HSE, 1993, for the investigation
of genetically modified organisms for vaccine manufacture. The
organisms involved were—E.coli K12, Vaccinia virus
(smallpox! and a carrier vector for gene-modified vaccines),
Francisella tularensis (Rabbit Fever!), Yersinia pestis
(plague), Salmonella typhimurium, Bacillus subtilis, Bacillus
brevis, Clostridium perfringens. This information has not
been disclosed to the Independent Panel.
All this supports the fears of the troops and
the evidence of the records that experimental and untested vaccines
could have been given to the UK and USA troops. It needs fully
investigating.
THE ADJUVANT
STORY
Adjuvants are administered to cause an enhanced
immunogenic response to a vaccine which otherwise might not afford
protection against the disease for which the vaccine is being
used. Anthrax vaccine is well known to be of low immunogenicity.
In the UK it was decided to use pertussis as an adjuvant. In the
USA no adjuvant was officially given but recently there have been
reports of the identification of squalene antibodies in the blood
of USA GWVs who received their vaccines and were deployed to the
Gulf and those who, although receiving the vaccines, were not
finally deployed. Two UK GWVs were also found to be positive for
these antibodies, Matsumoto, 1999, Rodriguez, 1999.
Squalene is a component of a widely used adjuvant,
MF 59, which has been much used in animal studies involving experimental
HIV vaccines. Its presence in GWVs indicates its use in undisclosed
experimental vaccines or as an unapproved adjuvant for anthrax.
Either way the troops have been used as experimental animals.
Furthermore, the findings in UK troops requires explanation.
What American vaccines were given to UK troops?
How many American troops received UK vaccines?
What comparison of the effects of these vaccines
has been made?
Again no discussion has taken place in the Independent
Panel. Squalene is known to cause major adverse effects in humans
when injected.
THE MYCOPLASMA
STORY
Garth and Nancy Nicolson, 1996, 1997, 1998,
in a series of peer reviewed papers, provide compelling evidence
of the role of mycoplasmas, particularly Mycoplasma fermentens
incognitus, in GWS/I. They have identified this organism in
~45 per cent of sick GWVs and developed an effective treatment,
using powerful antibiotics doxycycline, ciprofloxacin, clarythromycin
(but not penicillins) with suitable adjunct therapy. Initially
the Nicolsons received ridicule and persecution (the story is
well told by them in an article in "Criminal Politics",
1996). One extremely disturbing feature of their story is the
possible identification of a gene-modified mycoplasma which might
be part of an illicit or unknown BWs programme. A study of 1,000
GWVs using this regimen has just commenced in the USA.
The source of the mycoplasmas and other foreign
viruses could be vaccines prepared using animal cells or tissues.
These are well known and admitted in veterinary vaccines, Roth,
1998, Glickman, 1998.
No examination of UK veterans has been carried
out and no treatment on these lines offered.
HUMAN ENDOGENOUS
RETRO-VIRUSES
(HERVS)
Howard Urnovitz in the States has explored this
aspect of chronic disease. He has identified markers, RNA fragments,
of multiple myeloma (a bone marrow cancer) in some GWVs along
with a number of other unusual RNA fragments. These he sees as
indicative of disturbance of the human genome as a result of exposure
to toxic biological and/or chemical organisms and derivatives.
Such disturbances could give rise to new chronic diseases which
might be transmissible, Urnovitz, 1992, 1998.
TRANSMISSIBILTY
There are increasing reports of close family
members of GWVs contracting similar GWS/I. This points to some
infectious organism(s) which is/are transferred on prolonged and
close contact Thomas, 1998; Fudenberg, 1999; Van Kleist, 1997;
Nicholson, 1996.
THE CONSEQUENCES
OF COMPRESSED
MULTI-VACCINE
ADMINISTRATION
It is important to recognise the variety of
vaccines that were given to the GWVs. These included live vaccines
containing attenuated organisms, polio, yellow fever, smallpox,
oral typhoid (used in USA); whole dead organisms, cholera; plague;
sub-cellular components of organisms, anthrax, tetanus, meningitis,
pertussis, hepatitis B; immunoglobulins, hepititis A, botulinum
anti-toxin.
When the knowledge of the vaccine regimens given
to the troops became widely known an important paper appeared
in the British Medical Journal by Graham Rook and Alimuddin
Zumla. This argued that the vaccines administered would lead to
a considerable shift in the immune response from a balanced distribution
of Th1/Th2 cells to an unbalanced and dysfunctional increase in
Th2 cells with a significant suppression of Th1 cells. The outcome
of this change would be a shift from cell-mediated immunity to
an excessive humoral response. There would be a reactivation of
latent viruses such as Epstein-Barr virus, EBV, and herpes viruses,
with an increased susceptibility to adventitious infections, and
loss of important immune responses such as the control of viral
infections and the destruction of cancer cells. The development
of chronic autoimmune diseases would be facilitated. Organophosphates
are known to promote similar immune responses.
This pattern of infectious illness is found
in many GWVs. Nearly all have an active EBV infection. Many complain
of their inability to deal with previously common place infections—"I
catch everything that is going and it takes ages to shake things
off". In the USA, GWVs showed an unexpectedly poor response
to polio serotypes 2 and 3 not found in troops who had not been
vaccinated according to the Gulf War regimens. This is indicative
of a seriously compromised immune response to an effective and
well-established vaccine, Urnovitz, 1998, Thomas, 1998.
Among the GWVs autoimmune diseases have appeared,
Nass, 1999; multiple sclerosis-like illnesses, Sjorgren's syndrome,
rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus.
The latter is principally an autoimmune found in women but amongst
GWVs it has a high prevelance in men. Lou Gehrig's disease (amyotrophic
lateral sclerosis), also known as motor neurone diseases, is regarded,
by some as an auto-immune disease, that affects the neuromuscular
junction. It is much more common amongst GWVs than the normal
population, Burton, 1997.
Some of the organisms in these vaccines, eg
polio, measles, are known to populate and adversely stimulate
the lymphoid tissue of the gut thereby damaging the integrity
of the gut membranes in a manner that could extensively compromise
gut function.
Others are known to affect neural tissue. Recently,
in the USA, MRS (Magnetic Resonance Spectroscopy) has shown major
defects in key brain areas, eg the brain stem, of some GWVs, Haley
and Fleckenstein, 1999a.
We have no data on any of these aspects of immune
disorders in UK veterans. No work has been done.
CONCLUSIONS
(1) Many procedures were experimental and
did not obtain informed consent from the GWVs. This is both unacceptable
and breaches medical ethics;
(2) Pertussis (Whooping cough) as an unproven
adjuvant which had not been evaluated, and without the knowledge
of one of the main suppliers;
(3) Anthrax vaccine was unproven against
pneumonic infection and has shown to provide very limited protection;
(4) The immunological aspects of GWS/I have
not been effectively addressed to date. Both diagnostic procedures
and treatment possibilities remain unexplored;
(5) MRI, MRS, SPECT and PET scans should
be taken of sick GWVs to look for evidence of brain damage;
(6) Data on rare conditions, Lou Gehrig's
disease, nephrotic syndrome, systemic lupus erythematosus etc,
associated with possible immunological damage should be compiled
on a National Register.
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