The Three A's (Assumption) in Dapsone.
Supplied to me by Noel Benefield, thanks Noel
The trial of daily 25mg dapsone and 200mg Paludrine, in Vietnam, was accompanied by a number of assumptions.
No toxicology investigations were conducted prior to the observation trial period of late 1968. The first assumption was that because dapsone had been used in leprosy at a higher dose, no untoward effects were anticipated. (Black, Smithhurst)
Leprosy, a bacterial disease of genetically predisposed sufferers, has a high affinity to both dapsone and its metabolite. As a result dapsone in these patients is readily utilised and detoxified.
In the chemoprophylaxis of malaria, a preventative for a potential disease, the mechanism is markedly different. In this situation after the drug has been metabolised, in the blood cells it can be reconverted to the parent drug, which is returned to the liver and reoxidised in a systemic cycle. Known as the glutathione-dependant cycle, consisting of the actions of three amino acid groups, it acts as a body's antioxidant mechanism.
Assumption two in Vietnam was that the effectiveness of the addition of dapsone, to the existing regime of 200mg Paludrine, was a result of its amplification of Paludrine's efficacy against the parasite. (Rodgers) In fact the above mechanism was the reason for the remarkable reduction of cases of falciparum malaria during the observation trial in late 1968.
In 1992 the Australian Army reinvestigated the use of dapsone with 200mg paludrine daily. On this occasion the dapsone level was restricted to 10mg. No adverse effects were recorded in clinical trials, but it was found to in effective in field trials at 12.5mg. (Edstein) At these lower daily doses none of the participants could reach the half-life concentrations of dapsone, that would have been experienced by servicemen in Vietnam.
In Vietnam in early 1969 Australian authorities initiated the first toxicology trial of 25mg dapsone daily after the Americans had difficulties. The subsequent cases of agranulocytosis that occurred were explained by assumption three.(NZDLS 17 April 85) This was that the drug had been contaminated en route to Vietnam. Paradoxically these conditions were a result of metabolite cycling, the very mechanism that contributed to dapsone's efficacy against malaria.
These were not the only conditions experienced with dapsone in Vietnam. A small number are recorded as been having a possible association with dapsone. Many had been hospitalised for malaria, and conditions that would have been a result of dapsone were attributed to the disease. In all cases the pathologist always contradicted where the clinician suspected dapsone involvement . The widespread acceptance of assumption one amongst medical authorities at that time, denied factual investigation of the use of 25mgDapsone with 200mg Paludrine to determine if it was a safe chemoprophylaxis regime. One diagnostic tool that would have been useful in determining an association with dapsone, at that time, would have been a liver function test. But this simple tool was determined to be unnecessary in a war situation.(Fleming)
References:
Black "Malaria in the Australian Army in South Vietnam" Medical Journal of Australia June 1973
Smithhurst. "Dapsone induced agranulocytosis complicated by gram-negative septicaemia" Medical Journal of Australia March 1971.
Rodgers. Evidence presented to the Evatt Royal Commission.
Fleming. " Experiences with Malaria in the early phase of the Australian Army involvement in South Vietnam." Medical Journal of Australia 1974
Edstein. "Multiple-dose kinetics in healthy volunteers and in vitro antimalarial activity of proguanil plus dapsone" and "Malaria chemoprophylaxis using proguanil/dapsone combinations on the Thai- Cambodian border."
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