Relaxin is produced mainly in the ovary by the corpus luteum. During
pregnancy, it inhibits spontaneous contractions of the uterus, and makes
delivery easier by softening the cervix and elongating the pubic ligament.

In 1990, scientists discovered relaxin’s effect on the heart after injecting
anaesthetised rats with relaxin from pigs. They found not only that the
hormone increased the rats’ heart rate, but that there are specific binding
sites for the hormone in the animals’ heart muscle (atrial myocardium).

Prompted by this discovery, Hariclia Karikouris and his colleagues at
the University of Melbourne set out to investigate whether relaxin acts
directly on the heart or by releasing catecholamine hormones such as noradrenaline
from atrial tissue. The team studied the effects of synthetic human gene-2
relaxin (hR1x-2) on isolated rat atria which could be made to contract spontaneously
when a voltage was applied.

Karikouris’s team found that as the dose of relaxin increased so did
both the heart rate (chronotropic) and inotropic function, which measures
the force of the heart’s contractions. The researchers pre-treated one group
of rats with reserpine, a substance which depletes catecholamine (CA) stores,
and were able to show that the release of CA was responsible for only a
small part of the hRlx-2 stimulation of the heart (The Lancet, 2 May, p
1076).

The researchers found that the concentration of hRlx-2 required to produce
half its maximum effect (EC₅0) on the atria is only about 10
^-10 moles per litre. This makes it one of the most potent chronotropic
and inotropic agents known. It also supports the idea that the hormone exerts
its actions through specific receptors in the heart.

The researchers point out that the concentration of relaxin in the
blood rises during the first trimester of pregnancy, when a woman’s heart
rate increases by about 40 per cent. The hormone’s ability to increase the
rate and force of the heart could account for this.

Relaxin has a similar effect on the hearts of both male and female rats,
which suggests that its effects on the heart may be important outside
pregnancy. The hormone has yet to be isolated in the male rat. However,
it has been identified in the reproductive tract of men.

With this title and Merck and Glaxo as contestants, you could be forgiven
for expecting a blow-by-blow account of a no-holds-barred assault between
these two giants as Glaxo attempts to knock Merck from its position as the
premier – in money terms – purveyor of medicines to the world.

An author’s note, however, bids us raise our sights. As well as being
a book about the drugs industry, ‘its heroes and demons; . . . it is a story
about the soul of capitalism’. Written in the form of a morality play, with
three protagonists, the ‘demon’ takes the stage first. It is Hoffman La
Roche, Swiss originator of Valium, which ‘became the biggest and most profitable
drugs company ever’ in the 1960s, and a model for the industry. Even then,
‘before it blew the whole caboodle away in a whirlwind of misshapen desire,
Roche was a walking caricature of capitalist evil’.

Part Two, the centrepiece and largest section is headed, ‘The Aristocrat:
Merck’. Introduced many pages before in the introduction as a ‘square jawed
and clean cut’ hero, a description of the company runs: ‘Wherever Merck
goes, wherever it swanks and swerves, it carries with it a question: can
nice guys win? And it brings an answer in its baggage as well: of course
they can – look at us’. The final scene in this ‘act’ is called: The Philosopher
King.

‘The Incursor: Glaxo’ (the author’s villain) ends the play, the opening
chapter entitled ‘Badlands’ (‘extensive uncultivable eroded tracts in arid
areas’, according to the Concise Oxford Dictionary). Ironically, the company
had earlier been introduced as the most dramatic business success of the
decade: ‘From a lowly status it has progressed to become the UK’s fourth
largest company . . . ‘ Since this book was written, Glaxo doubled its share
price in 1991 and announced profits of £1.3 billion.

According to Matthew Lynn, Glaxo’s success is due entirely to its discovery,
development and selling of ranitidine (Zantac), a treatment for peptic ulcers
which reduces gastric acid secretion by blocking histamine (H₂)
receptors. The speed at which it overtook the first ever H₂-blocker,
cimetidine, invented by SKF, led other firms to follow suit. Among them
was a Japanese company from which Merck bought a licence to make and sell
famotidine (Pepcid), which is marketed in Britain by a Merck subsidiary.
This is a long-standing practice among drug companies. For example, Glaxo
acquired a licence 35 years ago from Merck for its steroid drug prednisolone.

Some see this step by Merck to get into the ulcer market as a response
to Glaxo’s backing out at the last moment from a deal with Merck to market
Zantac in the US. Glaxo then turned to Hoffman La Roche to do the job for
it on terms much more favourable than were on offer from Merck. In between,
in 1982, Merck agreed to take over North American licences on drugs manufactured
by the Swedish firm, Astra, the inventor of a new class of ulcer drugs,
known as the ‘proton pump inhibitors’, the first of which was omeprazole
(Losec).

So the ‘battle’ billed in the title is over which drug will dominate
the multimillion dollar ulcer market in 10 years’ time. Lynn believes, ‘Glaxo
is fated to replay the tragedy of Roche’, and cites as evidence Glaxo’s
efforts to queer the pitch for Losec from the start. Purple prose and all,
this experienced business journalist’s view of the anatomy of capitalism’s
soul is worth reading.

‘It is a possible explanation of the anomalous sudden deaths,’ says
John Morley, a pharmacologist at Sandoz Pharma in Basel, Switzerland, which
makes a different type of asthma drug. ‘It would explain why people who
inhale frequently while they wait for the ambulance are dead on arrival.’

Beta-2 agonists such as salbutamol, marketed as Ventolin, bring quick
relief during potentially fatal asthma attacks by expanding the airways
in the lungs, making breathing easier. However, there is evidence that patients
who take the drugs regularly may be making their asthma worse. Worried that
this may partly explain the recent increase in the number of deaths from
asthma, many doctors are encouraging sufferers to reduce the amount of beta-2
agonists they take.

Now, experiments on the effect of salbutamol in guinea pigs, carried
out by Morley, may explain why beta-2 agonists make things worse.

Salbutamol and other beta-2 agonists are manufactured as mixtures of
two isomers, molecules that are mirror images of one another. Only the left-handed
isomer of salbutamol expands airways. The right-handed isomer was believed
to be biologically inert. But Morley’s research suggests it may make airways
more sensitive to the allergens which cause the airways to narrow. He found
that injections of the right-handed isomer increased the tendency of the
airways of guinea pigs to constrict.

‘Patients using salbutamol or other beta-2 agonists to control their
asthma may be administering a noxious agent together with the active drug,’
he says.

‘However, although inhalation of the right-handed isomer of salbutamol
could be causing the airways to become hyper reactive, this detrimental
effect would usually be hidden by the relaxant left-handed isomer,’ says
Morley. He found no increased constriction of the airways with a fifty-fifty
mixture of left-handed and right-handed salbutamol.

But in further experiments, Morley found that with repeated high doses,
the beneficial effect of the left-handed isomer grows weaker but the harmful
effect of the right-handed isomer does not. Morley believes this may explain
the sudden and surprising deaths of some asthmatics. People with severe
asthma often respond to an attack by taking repeated doses of their beta-2
agonist.

Miles Wilson, a spokesman for Glaxo, makers of Ventolin, says the company
has not done this kind of experiment with pure isomers and sees no reason
to do so now.

Morley has also introduced salbutamol directly into the airways of guinea
pigs at doses similar to those used by humans. These experiments confirm
the findings of his injection experiments. He has also found evidence that
the effect may be common to other beta-2 agonists.

The CSM announced last week that its working group will concentrate
on whether beta-2 agonists should be recommended only for treatment of asthma
attacks. During an attack they bring quicker relief than any other type
of drug. However, doubt surrounds the effect beta-2 agonists have on the
airways of the lungs.

Clive Page, a pharmacologist at King’s College, London, says that the
constriction of the airways which makes it hard to breath in asthma, is
a natural defence against allergens such as cats’ hairs or the faeces of
house dust mites. The narrowed airways prevent more of the allergen from
entering.

Page argues that beta-2 agonists inhibit this mechanism, ultimately
causing greater harm. He says long-term use of the drugs may cause irreversible
damage to the walls of the airways (‘Are asthma drugs a cure that kills?’,
91av, 6 April).

The debate has sharpened since last December when the pharmaceuticals
company Glaxo launched the first in a new class of long-acting beta-2 agonists
called salmeterol. Some 250 reports of possible side effects from the drug
have been reported to the CSM, including 71 cases of worsening asthma and
48 deaths.

However, in the latest edition of its bulletin, Current Problems, the
CSM says: ‘Present evidence does not indicate that Serevent (salmeterol)
is associated with an important safety hazard.’

The bulletin warns that many cases of deteriorating asthma were the
result of doctors taking their patients off inhaled steroids, which damp
down inflammation in the lungs.

Underlying anxiety about beta-2 agonists stems from the steady increase
in the number of deaths from asthma since the mid 1970s. However research
published last week questions whether this rise is real. Ross Anderson and
David Strachan from St George’s Hospital Medical School in London reviewed
the latest figures from the Office of Population Censuses and Surveys in
England and Wales between 1979 and 1989. ‘We conclude that there is no evidence
for an increase in asthma mortality in children over this period,’ they
say.

Michael Rawlings, professor of pharmacology at the University of Newcastle
and a member of the CSM, says: ‘Our working party will be looking at the
OPCS statistics, to try to establish the real state of affairs.’

Strachan speculates that the perceived rise in asthma deaths among older
people is caused by misdiagnosis of other obstructive diseases of the airways.

People can reduce their intake by this amount simply be avoiding salty
food and not adding salt at the table say Malcolm Law and his colleagues
at St Bartholomew’s Hospital Medical School in London. If salt was also
left out of processed food, then deaths from strokes could be reduced by
some 39 per cent, and from heart attacks by 30 per cent. This would prevent
65 000 deaths a year in Britain.

These figures come from analysis of some 130 studies into the link between
blood pressure and salt intake. In three papers in the British Medical Journal
(vol 302, p 811) the researchers first estimate the quantitative relationship
between salt intake and blood pressure. They found that a 6-gram difference
in salt intake provoked a change in systolic blood pressure of 5 millimetres
of mercury among 15 to 19-year-olds. In 60 to 69-year-olds the difference
was twice that much.

Lowering salt intake by just 3 grams a day could, says Law, have more
effect than treatment with drugs.

Scientists have long known that weekly injections with the male hormone
testosterone can gradually reduce the number of sperm in semen until they
disappear altogether – a condition known as azoospermia. The WHO trials
set out to test whether inducing azoospermia can prevent pregnancy.

The researchers gave 271 men 200 milligrams of testosterone enanthate
weekly, injecting it into the muscle. Of these, 157 – about 60 per cent
– became azoospermic in an average of 120 days. The rest dropped out, 68
of them because they were not azoospermic after six months and the rest
for personal or medical reasons.

The 157 men then entered a year-long trial in which they continued the
injections as the sole contraceptive used by them and their partners. Another
38 dropped out before the year ended.

The failure rate for the method was negligible – 0.8 per 100 person-years,
compared with a rate between 0.2 and 0.4 for injectable female contraceptives
and 3 for oral contraceptives. By comparison, the failure rate for the intrauterine
device is 6 and for the condom, 12.

There was only one pregnancy among the couples involved in the trial.
All the samples of semen from the main involved were azoospermic. According
to the researchers, the pregnancy – later aborted – was from an extra-marital
affair. In 11 men, samples of semen showed that sperm were present, but
none of their partners became pregnant. After stopping the injections, the
average time until sperm reached their original concentration before injections
started was 6.7 months.

The report, published in The Lancet (vol 336, p 955), admits that weekly
injections, and the failure to make all men azoospermic, are major limitations
on the method. But long-acting preparations of the hormone could increase
the time between injections to as much as four months. A second stage of
the study will see whether conception can be stopped by reducing sperm in
semen, rather than removing it altogether.

Aila Rissanen and her colleagues at the Social Insurance Institute (SII)
in Helsinki carried out a study of 31 129 working people between the ages
of 25 and 64. They wanted to find out whether they could use the obesity
of a person as a reliable indicator of whether they might die before 65.
They also wanted to discover whether a person’s obesity might be useful
in predicting if they might be forced to retire early and require an invalidity
pension.

As a convenient measure of how obese a person was, the researchers used
the so-called body mass index, or BMI. A person’s BMI is simply their weight
(in kilograms) divided by their height (in metres squared). Rissanen and
her colleagues also used interviews and questionnaires to obtain information
about the social background, habits and health of the participants in the
study.

The researchers studied their subjects for a total of 346,000 ‘person
years’. In all, there were 2096 deaths among the sample, and 4706 disability
pensions were granted. In Finland, any person whose work capacity is deemed
to have been reduced by at least 40 per cent receives such a pension.

Rissanen and her colleagues found that the chance of a person needing
a disability pension increased with BMI, and that the increase was linear.
On the other hand, there was only slight correlation between mortality and
weight.

The researchers adjusted their data for the effect of a person’s age,
occupation, whether they smoked and the area in whey they lived. They found
that women with a BMI of 30 had twice the chance of needing a disability
pension as women with a BMI of less than 22.5. For men, the risk was one
and a half times as great. Men were no more likely to die before 60, but
for women the risk was 20 per cent greater.

According to Rissanen and her colleagues, an overweight person has an
increased risk of illness, a lower quality of life and is more likely to
lose earnings. If obesity is common in society, they say, it will mean that
more money will have to be spent on health. At the same time, productivity
of industry will be reduced.

With efficient weight control, say the researchers, ‘a substantial proportion
of all premature work disability pensions would not have been necessary’.

The findings emerge in the wake of reports last month in the Drug and
Therapeutic Bulletin – published by the consumer magazine Which? and sent
to all doctors – that manufacturers of commercially available suntan lotions
provide customers with inadequate information about the extent to which
the lotions will protect skin from harmful solar radiation that can cause
cancers.

Doctors usually make informed decisions about which medicines they should
prescribe by referring to the Monthly Index of Medical Specialities (MIMS)
or the British National Formulary (BNF), which is updated every six months.
However, investigations by 91av show that, like the labels on commercial
sunscreens, these two ‘bibles’ of pharmacology, which are sent to all general
practitioners, offer inadequate and confusing information on sunscreens.
In some cases, the information is incorrect.

There are two forms of harmful solar radiation – Ultraviolet A and Ultraviolet
B. Ultraviolet B causes sunburn, and both can cause skin cancers and wrinkling.
The main finding of the Drug and Therapeutics Bulletin in its investigations
of 15 sunscreen products was that in nine cases, the manufacturers had insufficient
data about the ability of their product to filter out UVA.

Moreover, the bulletin found, the so-called ‘Sun Protection Factors’
– numbers from 2 to 15 on product labels which in fact only reflect the
degree of protection that a suncream affords against UVB – were meaningless
because manufacturers of different products use different and incompatible
analytical tests to derive the values.

Manufacturers resist publishing a ‘Sun Protection Factor’ for UVA on
the grounds that the validity of the so-called ‘tape test’, once employed
to ascertain the figure, is now in doubt.

In the same way, both publications are vague about the properties of
the sunscreens prescribable through the National Health Service. MIMS names
products that ‘have some UVA protection as well as good UVB protection’,
but it gives no equivalent of the Sun Protection Factor for UVA in the relevant
entries. The BNF (No 18) says merely that the Sun Protection Factor ‘provides
some guidance on the degree of protection offered’, but mentions neither
UVA nor UVB in this context.

Two of the 10 sunscreens listed in MIMS ‘block only UVB’, yet the same
entries advise doctors that the products are appropriate for patients suffering
from photo-dermatoses (sensitivity of skin to ultraviolet light) or undergoing
radiotherapy. In both cases, it is essential to protect against UVB and
UVA, so the information in MIMS is insufficient for doctors to prescribe
appropriately.

The publications also contain inaccuracies relating to the active ingredients
in sunscreens. Three of the 10 sunscreens listed in MIMS rely on a reflectant
called titanium dioxide, though only one entry contains this information.
One of the three sunscreens containing titanium dioxide has zinc oxide incorrectly
listed as its active ingredient for reflecting harmful radiation. The same
error occurs in the BNF.

Gwen Parr of Ciba Geigy, a Swiss-based multinational which manufactures
the Piz-Buin range of sunscreens, agreed that the information about sunscreens
was ‘a bit of a mess’ that made it hard for doctors as well as lay people
to make a rational choice. Both she and Jean Gregory of Nicholas Laboratories
said that their firms were currently reviewing their sunscreen labelling
and considering how to improve the information on their products.

TESTS on fetal cells isolated from the mother’s blood in the first eight
weeks of pregnancy have revealed the sex of the fetus. The techniques, described
in The Lancet (28 July p 197), may also provide a way of identifying fetuses
suffering from serious genetic diseases without risking the mother or a
healthy fetus.

Other, ‘invasive’ techniques, such as amniocentesis and chorionic villus
sampling (CVS), carry a small (between 1 and 2 per cent) risk that the fetus
will abort spontaneously after the diagnostic procedure.

‘We now have the basis for routine prenatal screening programmes to
spot a range of genetic disorders such as Down’s syndrome and cystic fibrosis
as early as six weeks after conception,’ says Warren Jones, professor of
obstetrics and gynaecology at Flinders University in Adelaide and one of
the authors of the study.

The fetal cells in question are from the trophoblast, which forms the
wall of the blastocyst, the hollow ball of cells which is the early embryo.
Using monoclonal antibodies (MCAbs), Utz Mueller and his colleagues in Adelaide
isolated the fetal cells from blood samples by getting the cells to stick
to tiny magnetic beads coated with MCAbs derived from mice. Five such antibodies,
out of 6800 tested, bound tightly to the human trophoblast cells.

The genetic material from the cells, which is present in maternal blood
in relatively small quantities, was then replicated using the polymerase
chain reaction (PCR), a method of amplifying DNA exponentially. This is
so effective that the researchers could detect the male-determining Y-chromosome
from as few as three fetal white blood cells.

Until now, trophoblast cells for genetic analysis have been extracted
via a flexible tube inserted into the pregnant woman’s uterus, a technique
called chorionic villus sampling (CVS). The technique, which is used to
detect genetic disorders such as Down’s syndrome, carries a small risk to
the mother and healthy fetus. Amniocentesis, an alternative test that extracts
fetal cells from the amniotic fluid at about 18 weeks of pregnancy, also
carries a small risk.

Mueller’s study involved 12 women who had agreed to undergo CVS in early
pregnancy. Blood samples were taken first to avoid the possible release
of trophoblast cells into the circulation by the CVS. They then compared
the results of the tests on cells obtained by the two techniques. ‘We were
able to isolate the fetal cells as distinct from showing they are present,’
said Mueller. ‘It’s one thing to show they are there, it’s entirely another
thing to get them out.’

Tests on 11 of the 12 women correctly predicted the sex of seven male
and four female babies. But in one case the results of the blood test were
at odds with the CVS test. The researchers suspect that this was due to
contamination of the PCR procedure in the laboratory.

So before the test becomes routine, scientists and doctors will have
to organise trials to compare the accuracy of the new technique with the
conventional methods of CVS and amniocentesis, says Mueller. But plans for
marketing the test are already well underway. John Turner, head of Flinders
Technologies, said that the new test was one of the ‘most exciting dev elopments,
both technically and commercially, that I have ever encountered’.

Turner estimates that the new test, which relies on the specificity
of the monoclonal antibodies, could be ready for commercial use in about
two years. It should be worth Dollars A250 million (about Pounds sterling
125 million) a year. His company has the rights to commercialise the technology,
but is looking for investors abroad who could tackle the international market.

‘Already we have received expressions of interest from major organisations,’
said Turner. Patent applications have been taken out in all the major countries
of the world, he added.

People who suffer from hepatic encephalopathy have damaged livers, perhaps
by cirrhosis caused by alcoholism. Their brain function is impaired when
toxins which the liver is unable to remove accumulate in the body. Sufferers
are drowsy and confused, and they have difficulty writing. Ultimately, they
lapse into coma.

Kevin Mullen and colleagues at Case Western Reserve University’s medical
centre in Cleveland, Ohio, began looking for a benzodiazepine-like substance
in the body when they observed that the specific benzodiazepine-antagonist
known as flumazenil improved hepatic encephalopathy in rabbits. They subsequently
found that animals had the benzodiazepine-like substance in their blood.

In their latest work, Mullen and his colleagues compared blood, urine
and cerebrospinal fluid samples from people suffering from hepatic encephalopathy
with patients who had not taken any benzodiazepine for at least three months.
They found benzodiazepine activity to be higher in the people with the liver
disease than in the controls, with the highest values in patients with more
severe disease (The Lancet, 1990 ii, p 81).

The researchers cannot tell whether the benzodiazepine-like substance
is present in an amount which is sufficient to account for the central nervous
system effects seen in people with hepatic encephalopathy. They will be
able to tell this only when further experiments establish how the benzodiazepine-like
substance works.

Mullen and his colleagues have made some progress, however. They know
the molecular weight of the mystery substance is less than 1000 daltons.
They know that it is not a protein, that it is non-polar and that it is
stable when heated. It also shows many of the properties of the synthetic
benzodiazepines.

‘Because it is unlikely that mammals could synthesise heterocyclic molecules
containing chlorine atoms,’ Mullen says, ‘the most probable source is natural
benzodiazepines which enter the body in their native form from food or which
are generated from dietary precursors in the gut. We are carrying out experiments
to evaluate these hypotheses.’