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A COMPARISON OF THE EFFECTS OF INTRADERMAL CHLOROQUINE AND HISTAMINE IN HEALTHY BLACK SUBJECTS
TABLE OF CONTENT
LIST OF TABLES
LIST OF FIGURES
CHAPTER ONE: INTRODUCTION
CHAPTER TWO: METHODOLOGY
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
CHAPTER THREE: RESULTS
CHAPTER FOUR: DISCUSSION
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.
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).
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.
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).
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.
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 ventilate especially during anaesthesia.
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