SELECTED GENETIC RED-CELL MARKERS AND THE EPIDEMIOLOGY OF CHLOROQUINE-ASSOCIATED PRURITUS IN NIGERIA

Abstract

Anecdotal reports suggest that there may be a familial component to Chloroquine-associated pruritus (CAP). To test this hypothesis, the epidemiology of CAP was studied with respect to hemoglobin S (HbS) and glucose-6-phosphate dehydrogenase (G6PD) deficiency both of which are recognised genetic red-cell markers for blacks and for malaria. ABO blood groups which are also red-cell markers but not specific for blacks or malaria served as internal control. The prevalence of CAP was determined prospectively between January 1988 and June 1992 using cross-sectional survey in patients described below. The sample size was determined using EPI INFO 5. Only one individual per family was recruited. Field trips were made and a total of 1,315 patients were recruited into the study. A pretested questionnaire was used to collect information on personal details and family history of CAP from the recruited individuals. All the study patients except the school-children received Chloroquine at recruitment time and were observed directly for CAP 24 to 72 h later. Blood samples were then collected into sequestrene bottles (or filter papers for samples from distant areas). ABO blood groups, Hb and G6PD types were determined. Malaria parasite screening and full blood counts were also done on University College Hospital (UCH) samples. Prevalence of CAP among UCH patients was 124/300 (41.3%), pregnant women 23/55 (42.0%), urban school-children 85/150 (56.7%), rural school-children 61/121 (50.4%), rural preschool-children 33/151 (21.8%). Kano 16/121 (13.3%), Maiduguri 40/165 (24.2%), Potiskum 56/163 (49.6%) and Port-Harcourt 9/108 (8.3%). CAP increased progressively with age. CAP was more common in families of itchers than non-itchers. There was an association between cummulative Chloroquine intake and CAP. In all the populations studied, except among pregnant women, the sickle-cell trait was less common but G6PD deficiency was more common among itchers than non-itchers. By contrast however, ABO blood groups distribution was similar among itchers and non-itchers.

A simple, rapid, sensitive and highly reproducible high performance liquid chromatographic (HPLC) method was developed for the assay of Chloroquine and its main metabolite, desethylchloroquine. With the method it was demonstrated that the pharmacokinetics and urinary excretory pattern of Chloroquine and desethylchloroquine were similar in itchers (4 Hb AA and 3 Hb AS) and 8 non- itchers (4 Hb AA and 4 Hb AS) as well as in the Hb AA and Hb AS individuals. Nevertheless, there was evidence that the itchers were unable to metabolize Chloroquine as extensively as the non-itchers, as the ratio of the area under the curve (AUC) of the metabolite to that of the parent drug was lower in the itchers compared to the non-itchers. Also the peak concentration (Cmax) of Chloroquine was lower in Hb AS individuals when compared with Hb AA. However, bio-availability problem could not be ruled out in the Hb AS subjects. Seven of the 9 subjects prone to CAP actually itched, 6 of the 7 had residual Chloroquine (26.7± 11.2ng/ml) in zero hour plasma, whereas the remaining 1 itcher as well as the 2 who did not itch had no measurable quantity of Chloroquine in the zero hour plasma. It is concluded that CAP may be associated with certain genetic factors which include Hb and G6PD types.