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Prostate disease and the pharmaceutical industry
Alpha-blocking medicines
The prostate gland and bladder both contain smooth muscle
in which there are special structures called alpha receptors.
These are of several different kinds (alpha-1, alpha-2 etc.).
Alpha-blockers are medicines that bind to these receptors.
When this occurs, the smooth muscle of the prostate relaxes
and the pressure on the urethra is reduced. Relaxation of
the smooth muscle sphincter at the bladder neck also makes
it easier to urinate. Recent studies have also shown that
with more prolonged treatment, alpha-blockers may cause some
of the cells in the prostate to die, an observation that correlates
with the improvement in symptoms.
Alpha-blockers are successful in about two-thirds of patients.
Older compounds may take two to three weeks to work, but more
recent long-acting forms of alfuzosin and tamsulosin are quicker.
Because alpha receptors are also found in some parts of the
circulatory system, some people experience side effects such
as tiredness, dizziness and headache. Although these can usually
be managed, a major research effort has been the search for
alpha-blockers that bind more to alpha-1 receptors (the main
ones in the urinary tract) and less to the subtypes found
in other organs. These would be expected to have fewer side
effects. Further side effect reduction has been achieved by
the design of medicines that last longer in the body, and
by developing special preparations (dosage forms) that release
their active substance over a longer period of time.
Two of the earliest alpha-blockers used in BPH were indoramin
(SmithKline Beecham) and prazosin (Pfizer), both of which
have to be taken twice a day. Alfuzosin (Sanofi-Synthélabo)
has been developed in a special slow-release form called alfuzosinXL
and this compound, together with tamsulosin (Yamanouchi),
has some selectivity towards bladder and prostate alpha-1
receptors. Both need only to be taken once a day. This is
also true of the alpha-1 blocker, doxazosin (Pfizer), and
terazosin (Abbott). Controlled trials with alpha-blockers
show that they result in an average improvement in BPH symptoms
of about 60 per cent, and three-quarters of men treated will
derive significant benefit. Trials with doxazosin, alfuzosinXL
and terazosin suggest that their beneficial actions may extend
for longer than three years, although comparative placebo-controlled
trials have not been carried out. While the response to alpha-blockers
is good, up to 40 per cent of men may eventually need other
forms of treatment such as surgery.
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HOW MEDICINES ARE LICENSED
- Initial research
on new compounds is carried out in the laboratory,
using a wide variety of techniques.
- Promising
compounds are then studied in animals, to investigate
effects that cannot currently be predicted from the
computer and test tube studies.
- A
sequence of phases of clinical assessment in humans
follow strict guidelines.
- Phase
1 : a small number of healthy volunteers is given
the compound. These trials will determine some aspects
of how it works in humans and help to establish the
dose required.
- Phase
2 : a small number of patients with the condition
is given the medicine to assess both that it works
and that it does not produce unacceptable side-effects.
- Phase
3 : many more patients, perhaps several thousand,
take the medicine under supervision for an appropriate
period. It is tested in comparison with an established
treatment and/or a placebo. These studies are used
to establish the safety and efficacy of the new medicine.
- If
the results prove satisfactory in terms of quality,
efficacy and safety, the data gathered are presented
to the medicines evaluation authorities. If the authorities
are satisfied by the evidence, a marketing authorisation
is issued.
- Phase
4 : the newly-licensed medicine is studied in
large numbers of patients in general practice to assess
its clinical effectiveness.
- SAMM
(Safety Assessment of Marketed Medicines) studies
are sometimes initiated after the medicine has been
made available for doctors to prescribe and to help
identify any unforeseen side-effects. These may involve
many thousands of patients.
- GP
databases are also used to identify medicine safety
issues and to explore the potential for new and better
uses of medicines once the product is available for
prescription.
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