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A COMPARISON OF THE EFFECTS OF INTRADERMAL CHLOROQUINE AND
HISTAMINE IN HEALTHY BLACK SUBJECTS
TABLE OF CONTENT
CERTIFICATION
DEDICATION
ACKNOWLEDGEMENTS
LIST OF
TABLES
LIST OF
FIGURES
ABSTRACT
CHAPTER
ONE: INTRODUCTION
1.1.1 PRURITUS: DEFINITION, CAUSES AND
MODIFICATION BY DRUGS
1.1.2 CHLOROQUINE-INDUCED PRURITUS
1.3 BRIEF
PHARMACOLOGY OF DRUGS USED
1.3.1
CHLOROQUINE
1.3.2 HISTAMINE
1.3.3
D-TUBOCURARINE
CHAPTER
TWO: METHODOLOGY
2.1
SUBJECTS
2.2 OVERALL
DESIGN OF THE STUDY
2.3
PREPARATION OF DRUGS USED
2.4
PROCEDURE WITH EACH SUBJECT
2.5
EVALUATION OF SKIN REACTIONS
2.6 DATA
ANALYSIS
2.7
PRECAUTIONS
CHAPTER
THREE: RESULTS
CHAPTER
FOUR: DISCUSSION
REFERENCES
APPENDICES
ABSTRACT
The
acute local reactions of weal and flare induced by chloroquine in healthy black
subjects with a history of chloroquine in healthy black subjects with a history
of chloroquine induced pruritus was investigated. 30 out of an initial 50
subjects (both males and females) completed the study. Histamine, a classical
mediator of weal and flare was used as a source of comparison.
The drugs were injected
intradermally and concentrations of 0.2m1 each of 0.5mg/m1 Histamine, 10mg/m1
chloroquine, 50mg/m1 chloroquine, 100mg/m1 chloroquine and 0.9% saline (as
control) were given on the volar aspects of the foream. Local reactions of weal
and flare were measured 15 minutes after each injection by a planimetric method
while pruritus was measured by means of visual analogue scale for a period of
52 hours.
The results, analysed using 2-way
analysis of variance and student-t-test showed that both chloroquine and
Histamine induced significant weal and falre (p<0.05) as opposed to saline.
With respect to the overall mean percentages degree of pruritus, subsequent
tests using spaearman’s correlation showed significant positive correlation
between the weal induced by the 50mg/m1 chloroquine and percentage pruritus
(P<0.001). Also, a significant positive correlation was found between the
flare induced by all concentration fo chloroquine and percentage pruritus
(p>0.01). More interestingly, the flare areas induced by chloroquine in
subjects who experience pruritus with oral chloroquine were found to be
significantly greater than those who did not (P<0.5). This was not the case
with either Histamione or saline.
If further studies of this nature
yield similar results in both healthy and malarial subjects, senility and
specificity of the intradermal tests could be looked into with a view to developing
a diagnostic test for chloroquine-induced pruritus in malarial patients.
CHAPTER ONE
INTRODUCTION
1.1.1 PRURITUS: DEFINITION, CAUSES AND
MODIFICATION BY DRUGS
Pruritus is a term used when itching is the primary
complaint unaccompanied by visible evidence of lesions predisposing to itch.
Thus pruritus is actually a form of itching, but not all itching could be
termed ‘’pruritus’’.
Like any other
form of itching, pruritus is a sensation largely dependent on superficial nerve
endings, in an intact upper dermis and epidermis (weatheral et al, 1984).
Pruritus is a
poorly localised sensation mediated through class C nerve fibres. Impulses are
carried through the spinothalamic myelinated nerves in lateral spinothalamic
tracts and secondary neurones to the thalamus relay both pain and itch, and the
cerebral cortex can modify these responses (weatheral et al 1984).
Central
neurological and emotional psychiatric factors control the threshold to
pruritus (or to pain) and any other form of itching. Awareness is a complex
attribute modifying or intensifying the response to the itch.
However, itching
is usually worse when the skin is heated to normal body temperature and when
there is little else to distract the individual; these are features common at
night, hence most individuals that take chloroquine and who are susceptible to
chloroquine induced pruritus experience pruritus at its peak during the night
if they took this drug in the early hours of the day.
Agents that can
induce pruritus include histamine, kinins (speicailly endopeptidases),
serotonic and prostaglandins (Lindquist and ullberg, 1972. Weatheral et al, 1984).
1.1.2 CHLOROQUINE INDUCED PRUTITUS:
Generalised pruritus is a common side effect of oral
and parenteral chloroquine in black subjects and can be very disturbing in some
cases (Olatunde, 1977). This pruritus is thought to be due to an allergic
reaction but the exact mechanism is not clear. It hardly occurs in whites and
it may be related to binding of chloroquine to skin melanin (Lindquist and
Bulklberge, 1972) which, in susceptible individuals, may cause release of
chemical medaitors form cells such as mast cells. The mediators so released can
then cause pruritus with or without other allergic manifestations. Such
mediators may include histamine and prostaglandins (Herndon, 1975; weatherall
et al, 1984).
Although a
possible involvement of histamine in chloroquine induced pruritus have been speculated,
conclusive evidence as to this regard is lacking. Work done recently in our
laboratory (Abila and Ikueze, 1988) comparing the effects of single doses of
placebo, clemastine (2 mg), Jetotiten (2 mg) and prednisolone (20 mg) on
chloroquine induced pruritus in healthy volunteers showed that clemastine (an
antihistamine) and ketofen (a mediator release blocker) had no significant
effect on chloroquine induced pruritus when compared with placebo. By contrast,
the single dose of prednisolone produced about 50% reduction in pruritus
compared with placebo which was statistically significant (p<0.01) (see fig
10 and 1c).
These results
suggest that histamine may not be a major mediator of the choroquine-induced
pruritus. It is also possible that since this form of pruritus is much more prevalent
among blacks, it may be related to genetic mechanisms.
1.2
THE AIM OF THIS STUDY:
Although
histamine has not been shown to be involved in chloroquine induced pruritus,
and histamines are frequently so administered with chloroquine at extra cost
and with additional side effects such as drowsiness and dry mouth. The aim of
this study is to further examine the possible involvement of histamine in
chloroquine-induced pruritus by comparing the effects of intradermal injection
of histamine and chloroquine in healthy black subjects who experience
chloroquine induced pruritus.
1.2
BRIEF
PHARMACOLOGY OF DRUGS USED:
1.3.1 CHLOROQUINE:
This drug is a 4-aminoquinoline derivative and was the
drug of choice for the treatment of malaria the world over, before the
appearance of chloroquine- resistant falciparum malaria. However, it is still
one of the most frequently used antimalarial drugs for both acute attacks and
for prophylaxis. It has anti-inflammatory effects that have been useful in the
treatment of rheumatoid anthritis and discoid lupus erythematous. It is also
used in extra-intestinal amoebiasis. Would be taken orally or parenteral.
Chloroquine is
rapidly and almost completely absorbed from the gastro-intestinal tract, and a
small proportion of the administered dose (about 10-25% of the oral dose) is
excreted unchanged in the urine. Ti has a half-life of 5 days in the body. The
drug is almost 55% bound to plasma albumin and is rapidly removed form plasma
and concentrated in those tissues where active protein synthesis and cell
multiplication are greatest, the liver, spleen, kidneys, lungs and leukocytes
containing about 200-700 times the plasma concentration whereas the brain and spinal
cord contain only 10 -30 times the plasma concentration. It has a large volume
of distribution. Its excretion is quite slow, but is increased by acidification
or decreased by alkalinisation of the urine.
The mechanism of
action of the drug lies in a blockade of the enzymatic synthesis of DNA and RNA
in both mammalian and protozooal cells. The selective toxicity for the lalarial
parasites must therefore depend on a chloroquine concentrating mechanism in
parasitized cells (Katzung 1987). The drug forms a complex with DNA and
prevents it from acting as a template for its own replication or transcription
to RNA. This it does by inserting the quinolone ring between the base pairs of
the DNA double helix.
Side effects
occurring with antimalarial doses of the drug are usually reversible on
withdrawal of the drug and include headache, gastrointestinal disturbances,
diarrhoea, pruritus and skin eruptions, vertigo, malaria, anorexia, blurring of
vision. After high dosage, there may be macropapular eruptions, desquamation or
exfoliative lesions of the skin, alopecia or greying of the hair. Prolonged
administration of higher doses may lead to corneal and retinal changes which
may occur long after the drug has been withdrawn. The risk of retinopathy is
said to occur when the total cumulative dose ingested exceeds 100g (matindale,
1982). Rarely, blood disorders may occur and may include aplastic anaemia,
reversible agranulocytosis, thrombocytopenia and netropenia. Toxid psychoses
with hallucinations and agitation, EGG changes are frequent with high doses.
Congenital deafness and mental retardation have been reported in children born
to mothers who were taking large doses of cholorquine during pregnancy.
Because of high
concentration in the liver, it should be used with caution in patients with
hepartic disease. Ti should also be used with caution or not at all in the
presence of severe gastrointestinal, neurological or blood disorders (Goodman
et al 1985).
1.3.2 HISTAMINE:
Histamine
is a biologically active amide found in many tissues. It has complex
physiologic and pathologic effects. Its role in normal physiology is not
completely understood and it has no clinical application in the treatment of
disease (Katzung, 1987). However, compounds that selectively antagonize the
actions of this amine are of considerable clinical usefulness.
The drug was synthesized in 1907 and later
isolated from mammalian tissues. It is a 2-(-4-imidazolyl) ethylamine which
occurs in plants as well as in animal tissues. It is also a component of many
venoms and stinging secretions.
Histamine is formed by decarboxylation of the
amino acide L-histidine, a reaction catalysed in mammalian tissues by the
enzyme histamine decarboxylase. Pyridoxal phosphate is required as a cofactor.
Once formed histamine is either stored or rapidly activated by one of 2 amide
oxidases enzymes and by methylation. Very little histamine is excreted
unchanged. Most tissue histamine exists in bound form in granules in most cells
or basophils; the histamine content of many tissues is directly related to
their mast cell content (Katzung, 1987). The bound form of histamine is
inactive but many stimuli e.g morphine and d-tubocurarine can trigger the
release of mast cell histamine. Non mast cell histamine is also found in other
tissues like the brain and stomach.
Although marked species variation has been
observed in humans, histamine is an important mediator of immediate allergic
and inflammatory reactions, has an important role in gastric acid secretion,
and possibly functions as a neurotransmitter certain areas of the brain
(Katzung, 1987).
The biologic actions of histamine are exerted
by its combination with specific cellular receptors located in or on the
surface membrane. Two distinct types of receptors have been characterised, the
H1 and H2 receptors. Responses at both types of receptors
may involve alterations in membrane permeability to calcium or release of
calcium from internal stores. While H2 receptors mediated responses
involve an elevation of intracellular cyclic AMP, less compelling evidence
suggest, an association of elevated cyclic GMP with activation of H1
receptors.
Histamine exerts powerful effects on smooth and
cardiac muscle, on certain endothelical and nerve cells, as well as the
secretory cells of the stomach. However, sensitivity to histamine varies
greatly among species. In humans, it causes decrease in systolic and drastolic
blood pressures and an increase in heart rate. It also causes the classic
triple response of redness, weal and flare; causes bronchoconstriction, and
stimulation of other smooth muscles and exocrine glands like adrenal and
oxyntic glands.
Histamine is readily absorbed after parenteral
injection and acts rapidly when given by the subcutaneous or intramuscular
route. It has an evanescent action and is rapidly metabolised to inactive
products which are excreted in urine.
Overdosage with histamine is rare and symptoms
are generally not dangerous. However, massive doses cause intense headache,
flushing, profound fall of blood pressure, bronchospasm, dyspnoea, a metallic
taste, vomiting and diarhea.
1.3.3 D-TUBOCURARINE:
This
drug is a quarternary ammonium compound derived from the curare family with a
structure similar to that of acetylcholine. It is a non-depolarizing
neuromuscular blocking drug whose disappearance from the blood is characterized
by a rapid initial disappearance followed by a slower decay. The drug is
inactive orally, unless huge doses are ingested and is very poorly absorbed
form the gastrointestinal tract. Absorption is however quite adequate from
intramuscular sites.
Because of its ionization, the drug
does not cross membranes well and has a limited volume of distribution – 80 –
140m1/kg. D-tubocurarine is metabolised in variable amounts and about 50 – 60%
of an injected dose of the drug is excreted in the urine over a 24 – hour
period in humans. The exact route of excretion of the remainder is unclear
though it is presumed that biliary excretion accounts for most of it (Crankshaw
and Cohen, 1975). In patients with renal insufficiency, accumulation May occur
following multiple doses (Gibaldi et al, 1972). Insignificant amounts of the
drug cross the placenta late in pregnancy (Goodman et al, 1985).
In brief, d-tubocurarine combines with
the cholinergic receptors sites at the post-junction membrane and thereby
blocks completely the transmitter action of acetylcholine. There is evidence
that at higher doses, the drug enters the ion channel of the end-plate to
caus4e channel blockade, thus further weakening neuromuscular transmission.
The drug has a wide range of effects
many of which are mediated by autonomic and histamine receptors. It produces
hypotension, probably by release of histamine and sympathetic ganglion
blockade. It could also cause decreased tone and motility of the
gastrointestinal tract, bronchospasm, an excessive brochial and salivary
secretion, all of which appear to be caused by histamine release. When injected
intracutaneously or intra-arterially in man, it produces typical histamine-like
weals by the release of histamine.
The important untoward responses of d-tubocurarine are
prolonged apnoea cardiovascular collapse, and those resulting from histamine
release.
The drug has been used in the control of ventilative
especially during anaesthesia.
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