Ana
Lúcia Langer*
Muscular
dystrophies are genetics diseases that affect primary the muscular striated
issue. Duchenne Dystrophy Muscular is considered a lethal genetic disease
usually found during childhood. Because
of its seriousness, it should be aggressively treated and its progression
hindered. However, despite the fact that scientific advances have been made,
research in genetic and cellular therapies are not at this moment a treatment
effective for these pathologies. There are just options that can delay its
progression.
Among the variety of
medicines and dietetics supplements already tested, we have the amino acids,
calcium channel blockers, growth hormones, blockers of the growth hormone,
proteases inhibitors, vasodilators, Q10 coenzymes, catabolic steroids and
anabolic, imunosupressors, vitamins and many others.
Some of theses substances are promising, but research is needed before
these are used as a form of treatment. Others,
are given without regard to science or theory, many times they are given by the
family, because they have minimum adverse effects and positive effects suggested
in animal studies. Presently, there are a group of drugs, the steroids that have
already shown significant benefits for patients with some forms of muscular
dystrophy. However, because they may have significant side effects, patients on
this treatment must be monitored carefully. In spite of these side effects, the
corticoids represent the group of drugs that used alone show the best efficacy
in treatments for DMD/BMD. These drugs show the most benefit and should be started
immediately. The introduction of
these drugs to dystrophic patients should be aggressive and started early,
before the onset or signs of the disorder.
To
proceed, we will approach the main steroids used in dystrophy treatments,
beginning with prednisone, considered a model of corticoteraphy effects study
because of its existence in medical history and used most commonly.
Prednisone
The
prednisone, a catabolic steroid, tested in 1970, is showing itself extremely
promising in decreasing the muscular degeneration rhythm. It is the most
diffused for the Duchenne Muscular Dystrophy – DMD. In some cases, the
capacity of walking can be prorogated in 2 or more years. Besides, patients
treated can show significant improvement in respiratory function and better
functional preservation of the left ventricle.
The
catabolic steroids help the body to liberate glicosis and, so, mobilize energy
in answer of danger or stress. However, the exact mode that prednisone help
patients with DM is still unknown, and can be related to antiflamatory effects
or imunosupressors. The cytotoxic T cells that migrate for the retreat of the
hurted cells are delayed, minimizing the inflammatory answer and the fibrosis
decurrent. It should be salient that in muscular dystrophies, especially in
distrofinopaties (DMD and DMB), the inflamatory aggression has importance in
pathofisiology of the degeneration. Some researchers are speculating that
prednisone can also stimulate the production of muscular proteins.
Due to its effects
related for the sugar metabolism, catabolic steroids are also known as glicocorticoids. They
are produced and liberated by the outside portion of the adrenal (cortex) and,
so, also known as corticosteroids. The prednisone is the synthetic form of a
natural corticoid, the hidrocortisone.
Controlled tests confirm clearly the positive effects of prednisone. There are
strength increase and also muscular mass (though the CK enzyme levels can
continue unaltered) and preservation of the pulmonary and cardiac functions. On the other hand, when prednisone is no longer used, it
seems to have quick loss of the benefits obtained, and irrelevant to how much
time it was used.
The introduction to the start of steroid therapy is considered the sooner the
start the better. Some believe the
age to start steroid treatment is as early as 3 years of age.
There is no general consensus on the start time currently.
On the other hand, the side effects with the prednisone use can not be dismissed,
which can inhibit some patients to use it. Among them, we can cite:
a) Fluid retention
b)
Salt retention
c) Arterial Hypertension – we are seen this effect rarely.
d)
Cataracts
e) Diabetes – there are a glicose increase because of the glicocorticoid effect. In case there is this tendency, it can occur diabetes development.
f) Osteoporosis – It happens because the of the decrease of the calcium intestinal absorption; increase of urinary elimination, inhibition of the osteoblasts function, cells that contribute for the bone mass synthesis; stimulus to the function of other kind of bone cell, the osteoclasts, which channel its enzymes, stimulate bone reabsorption. Osteoporosis can be prevented using at the same time calcium supplements and D vitamin. In case of the continuing therapy, the preventing using drugs of the bifosphonate group (alendronate, risedronate) should be considered. Also important to note children with DMD/BMD can have osteoporosis already without the use of steroids. A bone density scan is advised prior to the use of steroids to have a baseline established.
g) Short stature – can be a benefic side effect in DM. It is known that dwarfs with DMD have a milder form of the disease.
h)
Increase of hunger – a strict diet should be imposed and monitored to
avoid obesity.
i) Behavior alterations – rarely
j) Imunosupressors effects – can be minimized using complete vaccine scheme.
k) Sexual hormones inhibition – there are, mainly in the continue use, delaying of the pubertal phase. At this phase there are much calcium absorption, which collaborates for the bone mass top, between 20 and 30 years in normal humans. The retardation at this moment supplies this absorption, collaborating as well for the tendency of few bones mass in patients.
l) Suppression of the supra-renal or adrenal glandule once this glandule stop producing his characteristical hormones, the cortisone and/or the aldosterone, when the therapeutic scheme of corticoid should be gradative because the risk of having adrenal insufficiency (or supra-renal) acute. Important symptoms to be aware and watch out for are when the patient shows weakness, nausea, vomit, pain and abdominal discomfort, mental confusion, low arterial pressure (arterial hypotension), fever, hipoglicemy, dehydratation, circulatory chock and coma. If these symptoms are not identified, the patient has his life in danger.
m) When there is daily treatment, and also because of the adrenal glandule suppression, there are no answers for stress, at this moment, for example, when the patient is scheduled for surgery or an infectious condition, it is necessary to increase more of the does for this hormone.
An
important strategy to help prevent the last two scenarios described above would
be to make sure all the patients are informed they can not suddenly stop the
medication. Educate the patient as
to the importance. Also, if possible, carry identification informing the use of
the steroids and need to increase the cortisone dosage in stress situations.
(Possibly a medical ID bracelet with the patients name and doctor’s
contact information).
All
clinic symptoms above described relate to the chronic use of corticoids form
what we call Cushing Syndrome. A condition, more commonly seen in females, due to
hyperadrenocorticism resulting from neoplasms of the adrenal cortex or the
anterior lobe of the pituitary, or to prolonged excessive intake of
glucocorticoids for therapeutic purposes. The symptoms and signs may include
rapidly developing adiposity of the face, neck, and trunk, kyphosis caused by
osteoporosis of the spine, hypertension, diabetes mellitus, amenorrhea (menstruation
absence),
hypertrichosis in females, impotence in males, dusky complexion with purple
markings, polycythemia (red
globule excess),
pain in the abdomen and back, and muscular wasting and weaknes.
http://129.195.254.70/cgi-bin/HONselect?browse+C14.907.934.142
There is no steriods schedule over another schedule
proven to be the most beneficial at this time.
This is still being researched as to which schedule is the best with the
least minimal side effects. Trying to answer some of the questions, the CIDD (Clinical
Investigation of Duchenne Dystrophy), formed by several
groups who tested prednisone in the last of 80’s, showed that:
a)
Prednisone increase strength
and muscular mass.
b)
The increase is detected in
the immediately in the first 10 days of treatment, showing an increase up to 3
months and maintaining after for about 18 months or more.
c)
Patients who use prednisone
for 3 years or more, the decrease of the strength and the function is slower
under this treatment, slowing the course of the natural history of the disease.
d) There is a delay in the decrease of the pulmonary function.
e) The most effective regimen is 0,75mg/kg/day.
f) Alternated days regimen does not maintain the strength as well as the daily regime and the side effects are not significantly different from the daily dose.
g) 0,3mg/kg/day regimen has been tested, but not determined as effective.
The
most common reason for the prednisone discontinuation or the dosis reduction is
the gain of weight.
Sansone, Dubowitz et al. described a regime where prednisone is prescribed (in the same dosis: 0,75mg/kg/day) for 10 days in the beginning of each month. They showed increase of strength until six months, with a slow decline in 12 to 18 months. Presently they are using a regime where the medication is used for 10 days, then there is an interruption for 10 days, again the drug is introduced for 10 days and so successively, with good effects. Several doctors support this therapeutic scheme because the effectiveness is shown and also the side effects are minimized. One suggestion would be to use the scheme of 10 days per month for young children and, from 3-4 years, since there is good development, change for 10 days using it and 10 days without it. The most frequent schemes can be anticipated since it has implication for good development.
Recently a group tested a new scheme with 10mg/kg/week for 3-6 months, giving 5mg/kg/day in two consecutive days, with results just as positive as daily scheme and with fewer side effects.
Deflazacort
Deflazacort,
another catabolic steroid, is given for the muscular dystrophy therapies,
specifically for DMD. Deflazacort is an oxazolone
derived from prednisone, with antiflamatories effects and imunosupresors
compared to it. The therapeutic equivalence is about 1,2mg of deflazacort for
1mg of prednisone. Because of the studies, the best dose recommended is
0,9mg/kg/day.
The delay of muscular degeneration effects and preservation of the
pulmonary and cardiac function were compared to prednisone. Another important
factor learned was the retardation of the surgery needed for scoliosis
correction.
Side effects noted,
it is observed that the patients that use deflazacort have less weight gain than
the ones who use prednisone, though the cataracts incidence is significantly
higher. The growth suppression is another important side effect of deflazacort,
which like prednisone, this side effect is considered beneficial in DM patients.
Some groups defend
deflazacort use in the daily scheme in place of the intermittent scheme with
prednisone, because they considered deflazacort more effective.
Another criteria that
should be considered in determining the kind of corticoid is economic situation.
Deflazacort is extremely more costly
than prednisone and, many times, discussing the benefit is not even an
affordable option for treatment.
Finally,
steroid therapy is the only proven way to delay the degenerative muscular
dystrophy effects. There is not a consensus in literature about which is the
best scheme. Personally, I have been trying to begin with an intermittent scheme,
because it has fewer side effects. In an intermediary phase of the disease or
when it becomes aggressive I talk about the advantages and disadvantages with my
patients. We make a decision to change the scheme or not.
Patients who are on the daily scheme must be monitored closely by their doctor.
Once a daily scheme is started you can not return to the other type of
schedules. The patient will suffer the loss of all the advantages
obtained from the daily schedule and a rapid decline of the benefits will happen.
* Vice-President of Brazilian Association of Muscular Dystrophy. Pediatrician from the Human Genome Study Center and Albert Einstein Hospital.