[Diluted injectable quinine in the intramuscular and intrarectal route: comparative efficacity and tolerance in malaria treatment for children ]. Intrarectal pharmacokinetics of two formulations of quinine in children with falciparum malaria. [Intrarectal administration of quinine: an early treatment for severe malaria in children?]. Intrarectal Quinimax (an association of Cinchona alkaloids) for the treatment of Plasmodium falciparum malaria in children in Niger: efficacy and pharmacokinetics. Dose-dependent resorption of quinine after intrarectal administration to children with moderate Plasmodium falciparum malaria. Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria. Rectal versus intravenous quinine for the treatment of childhood cerebral malaria in Kampala, Uganda: a randomized, double-blind clinical trial. An open randomized clinical study of intrarectal versus infused Quinimax for the treatment of childhood cerebral malaria in Niger. Quinine treatment of severe falciparum malaria in African children: a randomized comparison of three regimens.
The intramuscular (i.m.) route is generally used for treatment of childhood falciparum malaria in outlying health care units in Togo. The purpose of this randomized therapeutic trial was to compare the efficacy and tolerance of diluted injectable quinine administered by the i.m. versus intrarectal (IR) route. A total of 64 children ranging in age from 8 months to 15 years were treated, i.e. 32 for each administration route. All children presented uncomplicated falciparum malaria in association with vomiting in 30 cases, a single unrecurring seizure with postictal coma lasting less than 30 minutes in 25 patients, or prostration without neurological manifestations in 9. Injectable quinimax (an association of cinchona alkaloids) was diluted to a concentration of 60 mg base/ml for i.m. injection into the thigh and 30 mg base/ml for use by the IR route. Administration was performed every 12 hours for 72 hours at a dose of 12.5 mg/kg for patients in the i.m. group or at a dose of 15 mg/kg in the IR group. The anus and lower rectal mucosa were examined using an anal valve before and after treatment using the IR route. Analysis of mean temperature curves demonstrated no significant difference between the clinical effectiveness of quinimax administered by the i.m. versus IR route (p > 0.05). Similar effect were also observed on parasitemia which disappeared completely in all patients by the end of the 72-hour treatment. The main problems were insufficient product retention requiring re-administration in 25% of patients in IR group and residual pain at the injection site in 12.5% of patients in the i.m. group. Endoscopic examination revealed no evidence of ulceration or necrosis of the anorectal mucosa. These findings indicate that administration of diluted injectable quinine by IR route is an effective, well-tolerated alternative for treatment of childhood falciparum malaria. It should be used preferentially in outlying health care units in patients presenting severe malaria pending transfer to an hospital, or signs of "intermediate severity" such as hyperpyrexia, hyperparasitemia, unrepeated seizure, or intensive vomiting. To compare the intrarectal bioavailabilities of two parenteral formulations of quinine most available in French- (Cinchona alkaloid mixture) and English (hydrochloride salt) -speaking areas of Africa.
                The pharmacokinetics of quinine was investigated in four groups of 12 children with acute Plasmodium falciparum malaria receiving 8 mg/kg quinine base every 8 h either as hydrochloride salt or Cinchona alkaloid mixture by a slow 4-h intravenous infusion or intrarectal administration. Body temperature and parasitaemia were monitored, and blood quinine concentrations were measured by means of high-performance liquid chromatography.
                At 72 h, all the children were aparasitaemic and apyretic. Quinine C(max) values were higher after intravenous infusion of the hydrochloride salt and Cinchona alkaloid mixture (6.9+/-1.9 micro g/ml and 5.2+/-1.3 micro g/ml) than after intrarectal administration (3.5+/-1.4 micro g/ml and 3.1+/-1.6 micro g/ml), but t(max) values were similar (3.6+/-1.5, 4.2+/-1.0, 4.0+/-1.9, and 4.7+/-2.0 h, respectively). Intrarectal relative bioavailabilities of hydrochloride salt solution (57%) and Cinchona alkaloid mixture (62%) were similar.
                Whatever the parenteral formulation of quinine, the blood concentration-time profiles of quinine were similar after intrarectal administration. Intrarectal administration of hydrochloride salt solution is a possible mode of quinine delivery in remote rural areas of Africa. Delay for treatment of severe malaria is the cause of an important childhood mortality in Africa especially in rural zone when health facilities and accessibility are scarce. Intrarectal treatment is of particular interest in children as a non aggressive, painless and easy treatment. It can be used as early treatment and could decrease the lethality of severe malaria. We recently showed the kinetic profile, the optimal regimen and the clinical efficacy of intrarectal quinine (QIR) using Quinimax (Sanofi, Gentilly France) 20 mg/kg in solution with 2 ml of water. From 1994 to 1996 two open clinical trials were performed in Niger in children (2-15 years). QIR was compared with intraveinous infusion in cerebral malaria (n = 76) and with intramuscular quinine in severe malaria (n = 57). A three daily QIR administration (20 mg/kg followed by 15 mg/kg/8 h) was used in cerebral malaria; a two daily administration in severe malaria (30 mg/kg followed by 20 mg/kg/12 h). Symptomatic treatment was associated for hyperthermia, hypoglycemia, anemia and seizures. Results. In the cerebral malaria study 58 children presented a Blantyre coma score below 3. Four children in the IR group and 9 children in the infusion group died (P > 0.05). Evolution was similar in both treatment groups: temperature clearance (< 37.5 degrees C) 39.0 +/- 15.2 h and 37.1 +/- 16.5 h; return to consciousness 34.6 +/- 12.8 h and 33.0 +/- 14.1 h; decrease to 50% of the initial parasites count: 15.5 +/- 11.5 h and 13.8 +/- 10.0 h. Residual blood quinine concentrations at 48 hours were similar 7.4 +/- 3.7 mg/l and 7.2 +/- 2.9 mg/l. In the severe malaria study, the mortality was 0 and 7.6% in the QIR and IM group respectively (P > 0.005). Evolution was similar in both treatment groups: temperature clearance (< 37.5 degrees C) 38.7 +/- 22.8 h and 38.6 +/- 22.2 h; return to consciousness 26.8 +/- 13.9 h and 27.6 +/- 9.9 h for the 16 children in coma. The evolution under QIR treatment was also similar with that described with the other quinine routes. QIR allows an efficious treatment particularly when correct infusion cannot be performed. The efficacy, the simplicity and the good tolerance of QIR are of major concern to decrease the mortality of severe malaria due to delay for treatment and to decrease the side-effects due to intramuscular administrations of quinine in Africa. In an attempt to avoid the complications associated with intramuscular quinine administration, we assessed the intrarectal route. Sixty-six children aged from 2 to 10 years with Plasmodium falciparum malaria were included in the study, which took place in Niamey, Niger. Fifty-five children were given 20 mg/kg of the diluted injectable form of Quinimax (a quinine, quinidine, cinchonine, cinchonidine association) intrarectally. A further 11 children with malaria were treated with 12.5 mg/kg of the same Quinimax solution by the intramuscular route. All the children were treated twice a day for 3 d. Blood samples were drawn from 20 children (15 treated intrarectally and 5 intramuscularly) for a kinetic study. Both modes of administration were well tolerated. Mean fever clearance times (+/- standard errors) were 48.6 +/- 2.7 h and 35.9 +/- 2.2 h in the intrarectal and intramuscular groups, respectively (P = 0.05). Mean parasite clearance times (+/- standard errors) and mean times to achieve 50% reduction in parasitaemia (+/- standard errors) were similar after intrarectal (46.5 +/- 5.7 h and 7.8 +/- 0.9 h respectively) and intramuscular administration (27.4 +/- 3.6 h and 8.7 +/- 1.7 h, respectively). Tmax. after intrarectal administration (2.7 +/- 0.4 h) did not differ significantly from the value after intramuscular administration (1.1 +/- 0.6 h), but Cmax. and the area under the concentration-time curve from 0 to 48 h were lower (4.9 +/- 0.6 mg/L and 230.0 +/- 9.6 mg/L.h, respectively) than after intramuscular administration (9.1 +/- 1.2 mg/L and 356.0 +/- 4.2 mg/L.h, respectively) (P < 0.001). Compared to the intramuscular route, intrarectal Quinimax bioavailability was 40%.(ABSTRACT TRUNCATED AT 250 WORDS) The pharmacokinetics of increasing doses of an intrarectal Cinchona alkaloid combination containing 96.1% quinine, 2.5% quinidine, 0.68% cinchonine, and 0.67% cinchonidine (Quinimax) was compared to that of parenteral regimens in 60 children with moderate malaria. Quinine exhibited a nonlinear pharmacokinetics, suggesting a saturation of rectal resorption. When early rejections appeared, blood quinine concentrations decreased by 30 to 50% and were restored by an immediate half-dose administration of the drug. Rectal administration of doses of 16 or 20 mg/kg of body weight led to concentration-time profiles in blood similar to those of parenteral regimens and could be an early treatment of childhood malaria. 1. Three groups of seven children aged 2-14 years with acute uncomplicated Plasmodium falciparum malaria received 12.8 mg kg-1 quinine gluconate by the intrarectal route (new cream formulation) or 8 mg kg-1 Quinimax (a Cinchona alkaloid alkaloid combination) by the intramuscular or intravenous (4 h infusion) route every 8 h for 3 days. Clinical and parasitological status was similar in the three groups at enrolment. 2. At 36 h, body temperature of all children of the three groups was returned to normal and remained so until day 7. 3. The decrease in parasitaemia did not differ between the three groups and the time required for a 50% fall in parasitaemia relative to baseline was 12.3 +/- 5.4, 18.2 +/- 6.1 and 14.5 +/- 4.2 h in the intrarectal, intramuscular and intravenous treatment groups, respectively. Parasitaemia expressed as a percentage of initial values was not significantly different in the three groups after 48 h of treatment (7.4 +/- 16.0, 4.1 +/- 4.2 and 2.2 +/- 3.8% in the intrarectal, intramuscular and intravenous treatment groups, respectively). All the patients were aparasitaemic by day 7. 4. The tolerability of the three treatments was good; in particular, no rectal irritation was reported with the cream formulation. 5. The tmax occurred later after intrarectal (4.1 +/- 2.4 h) and intravenous infusion (3.8 +/- 0.5 h) than after intramuscular injection (1.6 +/- 1.3 h) (P = 0.02). Cmax was lower with the intrarectal (3.0 +/- 1.0 mg 1(-1)) and intramuscular routes (3.2 +/- 0.7 mg 1(-1)) than with the intravenous route (5.1 +/- 1.4 mg 1(-1)) (P = 0.003). Areas under the curve (AUC(0, 8 h)) were smaller with intrarectal (17.0 +/- 7 mg 1(-1) h) and intramuscular routes (19.4 +/- 4.8 mg 1(-1)) than with the intravenous route (27.8 +/- 8.2 mg 1(-1) h) (P = 0.02). The approximate bioavailability of intrarectal quinine from 0 to 8 h was 36% vs intravenous quinine and 51% vs intramuscular quinine. 6. The good tolerability and efficacy of this new intrarectal quinine formulation outweigh its low approximate bioavailability. This new approach might thus be a safe and effective alternative to intramuscular quinine injection for the treatment of children with acute uncomplicated Plasmodium falciparum malaria in the field. Although artemesinin derivatives are promising for the treatment of severe Plasmodium falciparum malaria, intravenous quinine remains the most affordable treatment. However, administration of intravenous quinine is often not feasible in rural areas in Africa because of the lack of simple equipment or trained staff. We compared the efficacy and safety of intrarectal quinine with those of intravenous quinine in the treatment of childhood cerebral malaria.
                In a randomized, double-blind clinical trial at Mulago Hospital (Kampala, Uganda), Uganda's national referral hospital, we studied 110 children aged 6 months to 5 years who had cerebral malaria. Patients were randomized to receive either intrarectal or intravenous quinine. Main outcome measures included parasite clearance time, fever clearance time, coma recovery time, time to sit unsupported, time to begin oral intake, time until oral quinine was tolerated, and death.
                Overall, there was no difference in the clinical and parasitological outcomes between the 2 groups (data are mean+/-standard deviation, intrarectal quinine group vs. intravenous quinine group): coma recovery time, 19.4+/-18.1 h versus 17.0+/-12.1 h; fever clearance time, 26.7+/-16.1 h versus 29.9+/-18.1 h; and parasite clearance time, 43.2+/-14.2 h versus 41.9+/-15.2 h. Mortality was similar in both groups; 4 of 56 patients in the intrarectal quinine group died, and 5 of 54 patients in the intravenous quinine group died (odds ratio, 1.3; 95% confidence interval, 0.3-5.2). Intrarectal quinine was well tolerated, and no major immediate adverse events occurred.
                Intrarectal quinine is efficacious and could be used as an alternative in the treatment of childhood cerebral malaria, especially in situations in which intravenous therapy is not feasible. The intrarectal route has been shown to be an alternative to parenteral therapy for the treatment of acute uncomplicated malaria. We conducted an open randomized clinical study of intrarectal Quinimax (a Cinchona alkaloids association) (20 mg/kg, then 15 mg/kg every 8 h) vs. intravenous Quinimax (8 mg/ kg infused over 4 h every 8 h) for 2 d in 76 children (39 in the intrarectal and 37 in the infusion groups) with cerebral falciparum malaria in Niger. This treatment was followed by oral chloroquine (10 mg/kg/d for 3 d). The primary end points of the study were fatal outcome and coma recovery time. In the intrarectal group, 35 children were cured (90%) and 4 died. In the infused group, 28 were cured (76%) and 9 died; mean coma recovery times were 34.6 h (SD = 12.8) and 33.0 h (SD = 14.1) for the intrarectal and infused groups, respectively. None of the differences was significant. Both treatments were well tolerated and no anal irritation was observed with intrarectal Quinimax. These findings suggest that intrarectal Quinimax can be an alternative to intravenous administration for rapid onset childhood cerebral malaria in the rural tropics, where the safety of parenteral administration cannot be guaranteed. The pharmacokinetics and effectiveness of three dosage regimens of quinine were studied in a group of 59 children with severe malaria. The children were randomized to receive high-dose intravenous or intramuscular quinine (20 mg salt/kg loading, then 10 mg salt/kg every 12 hr), or low-dose intravenous quinine (10 mg salt/kg loading, then 5 mg salt/kg every 12 hr). In the group receiving the high-dose intravenous regimen, mean high and low quinine concentrations were consistently greater than 10 and 6.5 mg/l, respectively. Peak concentrations as well as the time required to achieve them were similar in the intramuscular and high-dose intravenous groups. The low-dose intravenous quinine regimen resulted in mean peak concentrations greater than 6 mg/l and mean low concentrations greater than 3.5 mg/l. All blood concentrations exceeded the 99% in vitro inhibitory concentration (EC99) of 0.89 mg/l or less of quinine for 60 isolates of Plasmodium falciparum, which were taken from children with malaria during the same period. Judged by a number of clinical criteria, the response was better in patients receiving the high-dose than the low-dose intravenous regimen. The time taken to clear parasites with both the high-dose intravenous and intramuscular regimens were significantly shorter than those obtained in the low-dose group. We have also shown for the first time that the rate of parasite clearance can be directly related to the area under the quinine concentration versus time curve. This applied to all three quinine regimens (r = 0.4252, P less than 0.02; n less than or equal to 35). Five patients, two on the low-dose regimen, two on the intramuscular regimen, and one on the high-dose regimen, developed hypoglycemia after admission, but in these cases, insulin concentrations were correspondingly low. No significant quinine toxicity was observed in any of the cases. The high-dose intravenous quinine regimen described here may be optimal for treatment of severe falciparum malaria in areas of chloroquine resistance in Africa. Our data provide no justification for reducing the dose of quinine in the treatment of severe malaria in Africa. The intramuscular regimen could provide a satisfactory alternative in areas where intravenous administration might be delayed or is impossible.
We detected no difference in the effect on parasites and clinical illness for intrarectal quinine, but most trials were small. Pain may be less with intrarectal proprietary, buffered quinine preparations (made less acidic by adjustment of the pH to 4.5). Further larger trials in patients with severe malaria and in adults are required before the intrarectal route can be recommended.